Alzheimer’s disease: Mechanism and approach to cell therapy

International Journal of Molecular Sciences

Volumn 16, Issue 11, 2015, Pages 26417-26451

  Amemori, Takashi ^a   Jendelova, Pavla ^a,b   Ruzicka, Jiri ^a   Urdzikova, Lucia Machova ^a   Sykova, Eva ^a,b  

^a INSTITUTE OF EXPERIMENTAL MEDICINE   (Czech Republic)

^b CHARLES UNIVERSITY   (Czech Republic)

Author keywords

Alzheimer s disease; Amyloid ; Mesenchymal stem cells; Neural stem cells; Tau

Indexed keywords

ALZHEIMER DISEASE; ASTROCYTE; CANCER IMMUNIZATION; CANCER IMMUNOTHERAPY; DOWNSTREAM PROCESSING; GENE MUTATION; GLUCOSE METABOLISM; HUMAN; MESENCHYMAL STEM CELL; MICROGLIA; NEURAL STEM CELL; NONHUMAN; REVIEW; TUMOR MICROENVIRONMENT; AGING; AMYLOID PLAQUE; ANIMAL; BIOLOGICAL THERAPY; CYTOLOGY; DISEASE MODEL; ENERGY METABOLISM; GENETICS; GLIA; IMMUNOLOGY; IMMUNOTHERAPY; METABOLISM; MUTATION; ONSET AGE; PATHOLOGY; PROCEDURES; STEM CELL; STEM CELL TRANSPLANTATION;

AMYLOID BETA PROTEIN; TAU PROTEIN;

AGE OF ONSET; AGING; ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; ANIMALS; CELL- AND TISSUE-BASED THERAPY; DISEASE MODELS, ANIMAL; ENERGY METABOLISM; HUMANS; IMMUNOTHERAPY; MUTATION; NEUROGLIA; PLAQUE, AMYLOID; STEM CELL TRANSPLANTATION; STEM CELLS; TAU PROTEINS;

EID: 84946594802     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms161125961     Document Type: Review

References (355)

1. O’Brien, C. Auguste D. and Alzheimer’s disease. Science 1996, 273, 28. [CrossRef] [PubMed]
2. Gouras, G.K.; Almeida, C.G.; Takahashi, R.H. Intraneuronal Aβ accumulation and origin of plaques in Alzheimer’s disease. Neurobiol. Aging 2005, 26, 1235-1244. [CrossRef] [PubMed]
3. Goedert, M. Oskar Fischer and the study of dementia. Brain 2009, 132, 1102-1111. [CrossRef] [PubMed]
4. Maurer, K.; Volk, S.; Gerbaldo, H. Augaste D and Alzheimer’s disease. Lancet 1997, 349, 1546-1549. [CrossRef]
5. Graeber, M.B.; Kosel, S.; Egensperger, R.; Banati, R.B.; Muller, U.; Bise, K.; Hoff, P.; Moller, H.J.; Fujisawa, K.; Mehraein, P. Rediscovery of the case described by Alois Alzheimer in 1911: Historical, histological and molecular genetic analysis. Neurogenetics 1997, 1, 73-80. [CrossRef] [PubMed]
6. Graeber, M.B.; Kosel, S.; Grasbon-Frodl, E.; Moller, H.J.; Mehraein, P. Histopathology and APOE genotype of the first Alzheimer disease patient, Auguste D. Neurogenetics 1998, 1, 223-228. [CrossRef] [PubMed]
7. Muller, U.; Winter, P.; Graeber, M.B. A presenilin 1 mutation in the first case of Alzheimer’s disease. Lancet Neurol. 2013, 12, 129-130. [CrossRef]
8. Rupp, C.; Beyreuther, K.; Maurer, K.; Kins, S. A presenilin 1 mutation in the first case of Alzheimer’s disease: Revised. Alzheimers Dement. 2014, 10, 869-872. [CrossRef] [PubMed]
9. Anand, R.; Gill, K.D.; Mahdi, A.A. Therapeutics of Alzheimer’s disease: Past, present and future. Neuropharmacology 2014, 76, 27-50. [CrossRef] [PubMed]
10. Imtiaz, B.; Tolppanen, A.M.; Kivipelto, M.; Soininen, H. Future direction in Alzheimer’s disease from risk factors to prevention. Biochem. Pharmacol. 2014, 88, 661-670. [CrossRef] [PubMed]
11. Cacquevel, M.; Aeschbach, L.; Houacine, J.; Fraering, P.C. Alzheimer’s disease-linked mutations in presenilin-1 result in a drastic loss of activity in purified γ-secretase complexes. PLoS ONE 2012, 7, e35133. [CrossRef] [PubMed]
12. Bateman, R.J.; Aisen, P.S.; de Strooper, B.; Fox, N.C.; Lemere, C.A.; Ringman, J.M.; Salloway, S.; Sperling, R.A.; Windisch, M.; Xiong, C. Autosonal-dominant Alzheimer’s disease: A review and proposal for the prevention of Alzheimer’s disease. Alzheimers Res. Ther. 2011, 3, 1. [CrossRef] [PubMed]
13. Citron, M.; Westaway, D.; Xia, W.; Carlson, G.; Diehl, T.; Levesque, G.; Johnson-Wood, K.; Lee, M.; Seubert, P.; Davis, A.; et al. Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nat. Med. 1997, 3, 67-72. [CrossRef] [PubMed]
14. Selkoe, D.J. Alzheimer’s disease: Genes, proteins, and therapy. Physiol. Rev. 2001, 81, 741-766. [CrossRef] [PubMed]
15. Selfridge, J.E.; Lezi, E.; Lu, J.; Swerdlow, R.H. Role of mitochondrial homeostasis and dynamics in Alzheimer’s disease. Neurobiol. Dis. 2013, 51, 3-12. [CrossRef] [PubMed]
16. Mahley, R.W.; Nathan, B.P.; Pitas, R.E. Apolipoprotein E. Structure, function, and possible roles in Alzheimer’s disease. Ann. N. Y. Acad. Sci. 1996, 777, 139-145. [CrossRef] [PubMed]
17. Mahley, R.W.; Rall, S.C., Jr. Apolipoprotein E: Far more than a lipid transport protein. Annu. Rev. Genom. Hum. Genet. 2000, 1, 507-537. [CrossRef] [PubMed]
18. Beffert, U.; Stolt, P.C.; Herz, J. Functions of lipoprotein receptors in neurons. J. Lipid Res. 2004, 45, 403-409. [CrossRef] [PubMed]
19. Cedazo-Minguez, A. Apolipoprotein E and Alzheimer’s disease: Molecular mechanisms and therapeutic opportunities. J. Cell. Mol. Med. 2007, 11, 1227-1238. [CrossRef] [PubMed]
20. Roses, A.D. Apolipoprotein E alleles as risk factors in Alzheimer’s disease. Annu. Rev. Med. 1996, 47, 387-400[CrossRef] [PubMed]
21. Bertram, L.; Tanzi, R.E. The genetics of Alzheimer’s disease. Prog. Mol. Biol. Transl. Sci. 2012, 107, 79-100. [PubMed]
22. Slooter, A.J.; Cruts, M.; Kalmijn, S.; Hofman, A.; Breteler, M.M.; van Broeckhoven, C.; van Duijn, C.M. Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: The Rotterdam study. Arch. Neurol. 1988, 55, 964-968. [CrossRef]
23. Hollingworth, P.; Harold, D.; Sims, R.; Gerrish, A.; Lambert, J.C.; Carrasquillo, M.M.; Abraham, R.; Hamshere, M.L.; Pahwa, J.S.; Moskvina, V.; et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat. Genet. 2011, 43, 429-435. [CrossRef] [PubMed]
24. Naj, A.C.; Jun, G.; Beecham, G.W.; Wang, L.S.; Vardarajan, B.N.; Buros, J.; Gallins, P.J.; Buxbaum, J.D.; Jarvik, G.P.; Crane, P.K.; et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat. Genet. 2011, 43, 436-441. [CrossRef] [PubMed]
25. Lambert, J.C.; Ibrahim-Verbaas, C.A.; Harold, D.; Naj, A.C.; Sims, R.; Bellenguez, C.; Jun, G.; Destefano, A.L.; Bis, J.C.; Beecham, G.W.; et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 2013, 45, 1452-1458. [CrossRef] [PubMed]
26. Gandhi, S.; Wood, N.W. Genome-wide association studies: The key to unlocking neurodegeneration? Nat. Neurosci. 2010, 13, 789-794. [CrossRef] [PubMed]
27. Harold, D.; Abraham, R.; Haooingworth, P.; Sims, R.; Gerrish, A.; Hamshere, M.L.; Pahwa, J.S.; Moskvina, V.; Dowzell, K.; Williams, A.; et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat. Genet. 2009, 41, 1088-1093. [CrossRef] [PubMed]
28. Lambert, J.C.; Heath, S.; Even, G.; Campion, D.; Sleegers, K.; Hiltunen, M.; Combarros, O.; Zelenika, D.; Bullido, M.J.; Teavernier, B.; et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat. Genet. 2009, 41, 1094-1099. [CrossRef] [PubMed]
29. Chapuis, J.; Hansmannel, F.; Gistelinck, M.; Mounier, A.; van Cauwenberghe, C.; Kolen, K.V.; Geller, F.; Sottejeau, Y.; Harold, D.; Dourlen, P.; et al. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating Tau pathology. Mol. Psychiatry 2013, 18, 1225-1234. [CrossRef] [PubMed]
30. Antúnez, C.; Boada, M.; González-Pérez, A.; Gayán, J.; Ramírez-Lorca, R.; Marín, J.; Hernández, I.; Moreno-Rey, C.; Morón, F.J.; López-Arrieta, J.; et al. The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer’s disease. Genome Med. 2011, 3, 33. [CrossRef] [PubMed]
31. Bradshaw, E.M.; Chibnik, L.B.; Keenan, B.T.; Ottoboni, L.; Raj, T.; Tang, A.; Rosenkrantz, L.L.; Imboywa, S.; Lee, M.; von Korff, A.; et al. CD33 Alzheimer’s disease locus: Altered monocyte function and amyloid biology. Nat. Neurosci. 2013, 16, 848-850. [CrossRef] [PubMed]
32. Griciuc, A.; Serrano-Pozo, A.; Parrado, A.R.; Lesinski, A.N.; Asselin, C.N.; Mullin, K.; Hooli, B.; Choi, S.H.; Hyman, B.T.; Tanzi, R.E. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid ß. Neuron 2013, 78, 631-643. [CrossRef] [PubMed]
33. Karch, C.M.; Jeng, A.T.; Nowotny, P.; Cady, J.; Cruchaga, C.; Goate, A.M. Expression of novel Alzheimer’s disease risk genes in control and Alzheimer’s disease brains. PLoS ONE 2012, 7, e50976. [CrossRef] [PubMed]
34. Guerreiro, R.; Wojtas, A.; Bras, J.; Carrsquillo, M.; Rogaeva, E.; Majounie, E.; Cruchaga, C.; Sassi, C.; Kauwe, J.S.; Younkin, S.; et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 2013, 368, 117-127. [CrossRef] [PubMed]
35. Jonsson, T.; Stefansson, H.; Steinberg, S.; Jonsdottir, I.; Jonsson, P.V.; Snaedal, J.; Bjornsson, S.; Huttenlocher, J.; Levey, A.I.; Lah, J.J.; et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 2013, 368, 107-116. [CrossRef] [PubMed]
36. Rogaeva, E.; Meng, Y.; Lee, J.H.; Gu, Y.; Kawarai, T.; Zou, F.; Katayama, T.; Baldwin, C.T.; Cheng, R.; Hasegawa, H.; et al. The neuronal sortilin-related SORL1 is genetically associated with Alzheimer disease. Nat. Genet. 2007, 39, 168-177. [CrossRef] [PubMed]
37. Miyashita, A.; Koike, A.; Jun, G.; Wang, L.S.; Takahashi, S.; Matsubara, E.; Kawarabayashi, T.; Shoji, M.; Tomita, N.; Arai, H.; et al. SORL1 is genetically associated with late-onset Alzheimer’s disease in Japanese, Koreans and Caucasians. PLoS ONE 2013, 8, e58618. [CrossRef] [PubMed]
38. Jones, L.; Holmans, P.A.; Hamshere, M.L.; Harold, D.; Moskvina, V.; Ivanov, D.; Pocklington, A.; Abraham, R.; Hollingworth, P.; Sims, R.; et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease. PLoS ONE 2010, 5, e13950. [CrossRef] [PubMed]
39. De Strooper, B. Proteases and proteolysis in Alzheimer disease: A multifactorial view on the disease process. Physiol. Rev. 2010, 90, 465-494. [CrossRef] [PubMed]
40. Santos, C.R.A.; Cardoso, I.; Goncalves, I. Key enzymes and proteins in amyloid-ß production and clearance. In Alzheimer’s Disease Pathogenesis—Core Concepts, Shifting Paradigms and Therapeutic Targets; de la Monte, S., Ed.; InTech: Shanghai, China, 2011; pp. 53-86. [CrossRef] [PubMed]
41. Nikolaev, A.; McLaughlin, T.; O’Leary, D.D.; Tessier-Lavigne, M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 2009, 457, 981-989. [CrossRef] [PubMed]
42. Hardy, J.; Allsop, D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol. Sci. 1991, 12, 383-388. [CrossRef]
43. Selkoe, D.J. The molecular pathology of Alzheimer’s disease. Neuron 1991, 6, 487-498. [CrossRef]
44. Hardy, J.A. Higgins, G.A. Alzheimer’s disease: The amyloid cascade hypothesis. Science 1992, 256, 184-185. [CrossRef] [PubMed]
45. Hardy, J.; Selkoe, D.J. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science 2002, 297, 353-356. [CrossRef] [PubMed]
46. Giannakopoulos, P.; Herrmann, F.R.; Bussiere, T.; Bouras, C.; Kovari, E.; Perl, D.P.; Mossison, J.H.; Gold, G.; Hof, P.R. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology 2003, 60, 1495-1500. [CrossRef] [PubMed]
47. Naslund, J.; Haroutunian, V.; Mohs, R.; Davis, K.L.; Davies, P.; Greengard, P.; Buxbaum, J.D. Correlation between elevated levels of amyloid ß-peptide in the brain and cognitive decline. JAMA 2000, 283, 1571-1577. [CrossRef] [PubMed]
48. McLean, C.A.; Cherny, R.A.; Fraser, F.W.; Fuller, S.J.; Smith, M.J.; Beyreuther, K.; Bush, A.I.; Master, C.L. Soluble pool of Aß amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann. Neurol. 1999, 46, 860-866. [CrossRef]
49. Walsh, D.M.; Klyubin, I.; Fadeeva, J.V.; Cullen, W.K.; Anwyl, R.; Wolfe, M.S.; Rowan, M.J.; Selkoe, D.J. Naturally secreted oligomers of amyloid ß protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002, 416, 535-539. [CrossRef] [PubMed]
50. Cleary, J.P.; Walsh, D.M.; Hofmeister, J.J.; Schankar, G.M.; Kukskowski, M.A.; Selkoe, D.J.; Ashe, K.H. Natural oligomers of the amyloid-ß protein specifically disrupt cognitive function. Nat. Neurosci. 2005, 8, 79-84. [CrossRef] [PubMed]
51. Bitan, G.; Fradinger, E.A.; Spring, S.M.; Teplow, D.B. Neurotoxic protein oligomers—What you see is not always what you get. Amyloid 2005, 12, 88-95.
52. Zhao, W.Q.; de Felice, F.G.; Fernandez, S.; Chen, H.; Lambert, M.P.; Quon, M.J.; Krafft, G.A.; Klein, W.L. Amyloid ß oligomers induce impairment of neuronal insulin receptors. FASEB J. 2008, 22, 246-560. [CrossRef] [PubMed]
53. Zhao, W.Q. Alkon, D.L. Role of insulin and insulin receptor in learning and memory. Mol. Cell. Endocrinol.2001, 177, 125-134. [CrossRef]
54. Barry, A.E.; Klyubin, I.; McDonald, J.M.; Mably, A.J.; Farrell, M.A.; Scott, M.; Walsh, D.M.; Rowan, M.J. Alzheimer’s disease brain-derived amyloid-ß-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein. J. Neurosci. 2011, 31, 7259-7263. [CrossRef] [PubMed]
55. Um, J.W.; Nygaard, H.B.; Heiss, J.K.; Kostylev, M.A.; Stagi, M.; Vortmeyer, A.; Wisniewski, T.; Gunther, E.C.; Strittmatter, S.M. Alzheimer amyloid-ß oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat. Neurosci. 2012, 15, 1227-1235. [CrossRef] [PubMed]
56. Jin, M.; Shepardson, N.; Yang, T.; Chen, G.; Walsh, D.; Selkoe, D.J. Soluble amyloid ß-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc. Natl. Acad. Sci. USA 2011, 108, 5819-5824. [CrossRef] [PubMed]
57. Kayed, R.; Lasagna-Reeves, C.A. Molecular mechanisms of amyloid oligomers toxicity. J. Alzheimers Dis.2013, 33, S67-S78. [PubMed]
58. Pei, J.J.; Hugon, J. mTOR-dependent signalling in Alzheimer’s disease. J. Cell. Mol. Med. 2008, 12, 2525-2532. [CrossRef] [PubMed]
59. Foster, J.K.; Verdile, G.; Bates, K.A.; Martins, R.N. Immunization in Alzheimer’s disease: Naive hope or realistic clinical potential? Mol. Psychiatry 2009, 14, 239-251. [CrossRef] [PubMed]
60. Farlow, M.; Arnold, S.E.; van Dyck, C.H.; Aisen, P.S.; Snider, B.J.; Porsteinsson, A.P.; Friedrich, S.; Dean, R.A.; Gonzales, C.; Sethuraman, G.; et al. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement. 2012, 8, 261-271. [CrossRef] [PubMed]
61. Goure, W.F.; Krafft, G.A.; Jerecic, J.; Hefti, F. Targeting the proper amyloid-ß neuronal toxins: A path forward for Alzheimer’s disease immunotherapeutics. Alzheimers Res. Ther. 2014, 6, 42. [CrossRef] [PubMed]
62. Doody, R.S.; Thomas, R.G.; Farlow, M.; Iwatsubo, T.; Vellas, B.; Joffe, S.; Kieburtz, K.; Raman, R.; Sun, X.; Aisen, P.S.; et al. Alzheimer’s Disease Cooperative Study Steering Committee, Solanezumab Study Group. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N. Engl. J. Med. 2014, 370, 311-321. [CrossRef] [PubMed]
63. Siemers, E.R.; Sundell, K.L.; Carlson, C.; Case, M.; Sethuraman, G.; Liu-Seifert, H.; Dowsett, S.A.;Pontecorvo, M.J.; Dean, R.A.; Demattos, R. Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer’s disease patients. Alzheimers Dement. 2015. [CrossRef] [PubMed]
64. Wisniewski, T.; Goni, F. Immunotherapy for Alzheimer’s disease. Biochem. Pharmacol. 2014, 88, 499-507. [CrossRef] [PubMed]
65. Carrillo, M.C.; Brashear, H.R.; Logovinsky, V.; Ryan, J.M.; Feldman, H.H.; Siemers, E.R.; Abushakra, S.;Hartley, D.M.; Petersen, R.C.; Khachaturian, A.S.; et al. Can we prevent Alzheimer’s disease? Secondary "prevention" trials in Alzheimer’s disease. Alzheimers Dement. 2013, 9, 123-131. [CrossRef] [PubMed]
66. Lindwall, G.; Cole, R.D. Phosphorylation affects the ability of Tau protein to promote microtubule assembly. J. Biol. Chem. 1984, 259, 5301-5305. [PubMed]
67. Caceres, A.; Kosik, K.S. Inhibition of neurite polarity by Tau antisense oligonucleotides in primary cerebellar neurons. Nature 1990, 343, 461-463. [CrossRef] [PubMed]
68. Lee, V.M.; Goedert, M.; Trojanowski, J.Q. Neurodegenerative tauopathies. Annu. Rev. Neurosci. 2001, 24,1121-1159. [CrossRef] [PubMed]
69. Hong, M.; Zhukareva, V.; Vogelsberg-Ragaglia, V.; Wszolek, Z.; Reed, L.; Miller, B.I.; Geschwind, D.H.;Bird, T.D.; McKeel, D.; Goate, A.; et al. Mutation-specific functional impairments in distinct Tau isoforms of hereditary FTDP-17. Science 1998, 282, 1914-1917. [CrossRef] [PubMed]
70. Garcia, M.L.; Cleveland, D.W. Going new places using an old MAP: Tau, microtubules and humanneurodegenerative disease. Curr. Opin. Cell Biol. 2001, 13, 41-48. [CrossRef]
71. Gomez-Isla, T.; Hollister, R.; West, H.; Mui, S.; Growdon, J.H.; Petersen, R.C.; Parisi, J.E.; Hyman, B.T. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann. Neurol. 1997, 41, 17-24. [CrossRef] [PubMed]
72. Lasagna-Reeves, C.A.; Castillo-Carranza, D.L.; Sengupta, U.; Guerrero-Munoz, M.J.; Kiritoshi, T.; Neugebauer, V.; Jackson, G.R.; Kayed, R. Alzheimer brain-derived Tau oligomers propagate pathology from endogenous Tau. Sci. Rep. 2012, 2, 700. [CrossRef] [PubMed]
73. Berger, Z.; Roder, H.; Hanna, A.; Carlson, A.; Rangachari, V.; Yue, M.; Wszolek, Z.; Ashe, K.; Knight, J.;Dickson, D.; et al. Accumulation of pathological Tau species and memory loss in a conditional model of tauopathy. J. Neurosci. 2007, 27, 3650-3662. [CrossRef] [PubMed]
74. Ballatore, C.; Lee, V.M.; Trojanowski, J.Q. Tau-mediated neurodegeneration in Alzheimer’s disease andrelated disorders. Nat. Rev. Neurosci. 2007, 8, 663-672. [CrossRef] [PubMed]
75. Yoshiyama, Y.; Higuchi, M.; Zhang, B.; Huang, S.M.; Iwata, N.; Saido, T.C.; Maeda, J.; Suhara, T.;Trojanowski, J.Q.; Lee, V.M. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 2007, 53, 337-351. [CrossRef] [PubMed]
76. Sergeant, N.; Delacourte, A.; Buee, L. Tau protein as a differential biomarker of tauopathies.Biochim. Biophys. Acta 2005, 1739, 179-197. [CrossRef] [PubMed]
77. Wilhelmsen, K.C.; Lynch, T.; Pavlou, E.; Higgins, M.; Nygaard, T.G. Localization of disinhibition-dementia-parkinsonism-amyotrophy complex to 17q2-22. Am. J. Hum. Genet. 1994, 55, 1159-1165. [PubMed]
78. Goedert, M. Tau gene mutations and their effects. Mov. Disord. 2005, 12, 45-52.
79. Small, S.A.; Duff, K. Linking Aß and Tau in late-onset Alzheimer’s disease: A dual pathway hypothesis.Neuron 2008, 60, 534-542. [CrossRef] [PubMed]
80. Castellani, R.J.; Perry, G. The complexities of the pathology—pathogenesis relationship in Alzheimerdisease. Biochem. Pharmacol. 2014, 88, 671-676. [CrossRef] [PubMed]
81. Holmes, C.; Boche, D.; Wilkinson, D.; Yadegarfar, G.; Hopkins, V.; Bayer, A.; Jones, R.W.; Bullock, R.;Love, S.; Neal, J.W.; et al. Long-term effects of Aß42 immunisation in Alzheimer’s disease: Follow-up of a randomised, placebo-controlled phase I trial. Lancet 2008, 372, 216-223. [CrossRef]
82. Rosenmann, H.; Grigoriadis, N.; Karussis, D.; Boimel, M.; Touloumi, O.; Ovadia, H.; Abramsky, O. Tauopathy-like abnormalities and neurologic deficits in mice immunized with neuronal Tau protein. Arch. Neurol. 2006, 63, 1459-1467. [CrossRef] [PubMed]
83. Boutajangout, A.; Ingadottir, J.; Davies, P.; Sigurdsson, E.M. Passive immunization targeting pathologicalphospho-Tau protein in a mouse model reduces functional decline and clears Tau aggregates from the brain. J. Neurochem. 2011, 118, 658-667. [CrossRef] [PubMed]
84. Chai, X.; Wu, S.; Murray, T.K.; Kinley, R.; Cella, C.V.; Sims, H.; Buckner, N.; Hanmer, J.; Davies, P.;O’Neill, M.J.; et al. Passive immunization with anti-Tau antibodies in two transgenic models: Reduction of Tau pathology and delay of disease progression. J. Biol. Chem. 2011, 286, 34457-34467. [CrossRef] [PubMed]
85. Morley, J.E.; Farr, S.A. The role of amyloid-ß in the regulation of memory. Biochem. Pharmacol. 2014, 88, 479-485. [CrossRef] [PubMed]
86. Muller, U.C.; Zheng, H. Physiological functions of APP family proteins. Cold Spring Harb. Perspect. Med. 2012, 2. [CrossRef] [PubMed]
87. Ke, Y.D.; Suchowerska, A.K.; van der Hoven, J.; de Silva, D.M.; Wu, C.W.; van Eersel, J.; Ittner, A.; Ittner, L.M. Lessons from Tau-deficient mice. Int. J. Alzheimers Dis. 2012, 2012. [CrossRef] [PubMed]
88. Taylor, R.C.; Dillin, A. Aging as an event of proteostasis collapse. Cold Spring Harb. Perspect. Biol. 2011, 3. [CrossRef] [PubMed]
89. Schroder, M.; Kaufman, R.J. The mammalian unfolded protein response. Annu. Rev. Biochem. 2005, 74, 739-789. [CrossRef] [PubMed]
90. Urra, H.; Dufey, E.; Lisbona, F.; Rojas-Rivera, D.; Hetz, C. When ER stress reaches a dead end. Biochim. Biophys. Acta 2013, 1833, 3507-3517. [CrossRef] [PubMed]
91. Salminen, A.; Kauppinen, A.; Suuronen, T.; Kaarniranta, K.; Ojala, J. ER stress in Alzheimer’s disease: A novel neuronal trigger for inflammation and Alzheimer’s pathology. J. Neuroinflamm. 2009, 6, 41. [CrossRef] [PubMed]
92. Li, G.; Mongillo, M.; Chin, K.T.; Harding, H.; Ron, D.; Marks, A.R.; Tabas, I. Role of ERO1-a-mediated stimulation of inositol 1,4,5-tirphoate receptor activity in endoplasmic reticulum stress-induced apoptosis. J. Cell Biol. 2009, 186, 783-792. [CrossRef] [PubMed]
93. Urano, F.; Wang, X.; Bertolotti, A.; Zhang, Y.; Chung, P.; Harding, H.P.; Ron, D. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 2000, 287, 664-666. [CrossRef] [PubMed]
94. Sekine, Y.; Takeda, K.; Ichijo, H. The ASK1-MAP kinase signaling in ER stress and neurodegenerative diseases. Curr. Mol. Med. 2006, 6, 87-97. [CrossRef] [PubMed]
95. Kelleher, I.; Garwood, C.; Hanger, D.P.; Anderton, B.H.; Noble, W. Kinase activities increase during the development of tauopathy in htau mice. J. Neurochem. 2007, 103, 2256-2267. [CrossRef] [PubMed]
96. Ploia, C.; Antoniou, X.; Sclip, A.; Grande, V.; Cardinetti, D.; Colombo, A.; Canu, N.; Benussi, L.; Ghidoni, R.;Forloni, G.; et al. JNK plays a key role in Tau hyperphosphorylation in Alzheimer’s disease models.J. Alzheimers Dis. 2011, 26, 315-329. [PubMed]
97. Cuanalo-Contreras, K.; Mukherjee, A.; Soto, C. Role of protein misfolding and proteostasis deficiency in protein misfolding diseases and aging. Int. J. Cell Biol. 2013, 2013. [CrossRef] [PubMed]
98. Vallabhapurapu, S.; Karin, M. Regulation and function of NF-kappaB transcription factors in the immune system. Annu. Rev. Immunol. 2009, 27, 693-733. [CrossRef] [PubMed]
99. Rossner, S.; Sastre, M.; Bourne, K.; Lichtenthaler, S.F. Transcriptional and translational regulation of BACE1 expression—Implications for Alzheimer’s disease. Prog. Neurobiol. 2006, 79, 95-111. [CrossRef] [PubMed]
100. Resende, R.; Moreira, P.I.; Proenca, T.; Deshpande, A.; Busciglio, J.; Pereira, C.; Oliveira, C.R. Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. Free Radic. Biol. Med. 2008, 44, 2051-2057. [CrossRef] [PubMed]
101. Morawe, T.; Hiebel, C.; Kern, A.; Behl, C. Protein homeostasis, aging and Alzheimer’s disease. Mol. Neurobiol. 2012, 46, 41-54. [CrossRef] [PubMed]
102. Huang, Y.; Mucke, L. Alzheimer mechanisms and therapeutic strategies. Cell 2012, 148, 1204-1222. [CrossRef] [PubMed]
103. Kakimura, J.; Kitamura, Y.; Takata, K.; Umeki, M.; Suzuki, S.; Shibagaki, K.; Taniguchi, T.; Nomura, Y.; Gebicke-Haerter, P.J.; Smith, M.A.; et al. Microglial activation and amyloid-ß clearance induced by exogenous heat-shock proteins. FASEB J. 2002, 16, 601-603. [CrossRef] [PubMed]
104. Koren, J., III; Jinwal, U.K.; Lee, D.C.; Jones, J.R.; Shults, C.L.; Johnson, A.G.; Anderson, L.J.; Dickey, C.A. Chaperone signalling complexes in Alzheimer’s disease. J. Cell. Mol. Med. 2009, 13, 619-630. [CrossRef] [PubMed]
105. Wilhelmus, M.M.; de Waal, R.M.; Verbeek, M.M. Heat shock proteins and amateur chaperones in amyloid-ß accumulation and clearance in Alzheimer’s disease. Mol. Neurobiol. 2007, 35, 203-216. [CrossRef] [PubMed]
106. Jinwal, U.K.; O’Leary, J.C., III; Borysov, S.I.; Jones, J.R.; Li, Q.; Koren, J., III; Abisambra, J.F.; Vestal, G.D.; Lawson, L.Y.; Johnson, A.G.; et al. Hsc70 rapidly engages Tau after microtubule destabilization. J. Biol. Chem. 2010, 285, 16798-16805. [CrossRef] [PubMed]
107. Sahara, N.; Murayama, M.; Mizoroki, T.; Urushitani, M.; Imai, Y.; Takahashi, R.; Murata, S.; Tanaka, K.; Takashima, A. In vivo evidence of CHIP up-regulation attenuating Tau aggregation. J. Neurochem. 2005, 94, 1254-1263. [CrossRef] [PubMed]
108. Dickey, C.A.; Koren, J.; Zhang, Y.J.; Xu, Y.F.; Jinwal, U.K.; Birnbaum, M.J.; Monks, B.; Sun, M.; Cheng, J.Q.; Patterson, C.; et al. Akt and CHIP coregulate Tau degradation through coordinated interactions. Proc. Natl. Acad. Sci. USA 2008, 105, 3622-3627. [CrossRef] [PubMed]
109. Martin, M.; Dotti, C.G.; Ledesma, M.D. Brain cholesterol in normal and pathological aging. Biochim. Biophys. Acta 2010, 1801, 934-944. [CrossRef] [PubMed]
110. Wang, H.; Eckel, R.H. What are lipoproteins doing in the brain? Trends Endocrinol. Metab. 2014, 25, 8-14. [CrossRef] [PubMed]
111. Wood, W.G.; Schroeder, F.; Igbavboa, U.; Avdulov, N.A.; Chochina, S.V. Brain membrane cholesterol domains, aging and amyloid ß-peptides. Neurobiol. Aging 2002, 23, 685-694. [CrossRef]
112. Ariga, T.; Wakade, C.; Yu, R.K. The pathological roles of ganglioside metabolism in Alzheimer’s disease: Effects of gangliosides on neurogenesis. Int. J. Alzheimers Dis. 2011, 2011, 193618. [CrossRef] [PubMed]
113. Kakio, A.; Nishimoto, S.I.; Yanagisawa, K.; Kazutsumi, Y.; Matsuzaki, K. Cholesterol-dependent formation on GM1 ganglioside-bound amyloid ß-protein, an endogenous seed for Alzheimer amyloid. J. Biol. Chem. 2001, 276, 24985-24990. [CrossRef] [PubMed]
114. Fantini, J.; Yahi, N.; Garmy, N. Cholesterol accelerates the binding of Alzheimer’s ß-amyloid peptide to ganglioside GM1 through a universal hydrogen-bond-dependent sterol tuning of glycolipid conformation. Front. Physiol. 2013, 4, 120. [CrossRef] [PubMed]
115. Yuyama, K.; Yanagisawa, K. Sphingomyelin accumulation provides a favorable milieu for GM1 ganglioside-induced assembly of amyloid ß-protein. Neurosci. Lett. 2010, 481, 168-172. [CrossRef] [PubMed]
116. Allen, J.A.; Halverson-Tamboli, R.A.; Rasenick, M.M. Lipid raft microdomains and neurotransmitter signalling. Nat. Rev. Neurosci. 2007, 8, 128-140. [CrossRef] [PubMed]
117. Hanzal-Bayer, M.F.; Hancock, J.F. Lipid rats and membrane traffic. FEBS Lett. 2007, 581, 2098-2104. [CrossRef] [PubMed]
118. Cordy, J.M.; Hooper, N.M.; Turner, A.J. The involvement of lipid rafts in Alzheimer’s disease. Mol. Membr. Biol. 2006, 23, 111-122. [CrossRef] [PubMed]
119. Kojro, E.; Gimpl, G.; Lammich, S.; Marz, W.; Fahrenholz, F. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the a-secretase ADAM 10. Proc. Natl. Acad. Sci. USA 2001, 98, 5815-5820. [CrossRef] [PubMed]
120. Ehehalt, R.; Keller, P.; Haass, C.; Thiele, C.; Simons, K. Amyloidogenic processing of the Alzheimer ß-amyloid precursor protein depends on lipid rafts. J. Cell Biol. 2003, 160, 113-123. [CrossRef] [PubMed]
121. Hicks, D.A.; Nalivaeva, N.N.; Turner, A.J. Lipid rafts and Alzheimer’s disease: Protein-lipid interactions and perturbation of signaling. Front. Physiol. 2012, 3, 189. [CrossRef] [PubMed]
122. Grimm, M.O.; Kuchenbecker, J.; Rothhaar, T.L.; Grosgen, S.; Hundsdorfer, B.; Burg, V.K.; Friess, P.; Muller, U.; Grimm, H.S.; Riemenschneider, M.; et al. Plasmalogen synthesis is regulated via alkyl-dihydorxyacetonephosphate-synthase by amyloid precursor protein processing and is affected in Alzheimer’s disease. J. Neurochem. 2011, 116, 916-925. [CrossRef] [PubMed]
123. Rothhaar, T.L.; Grosgen, S.; Haupenthal, V.J.; Burg, V.K.; Hundsdorfer, B.; Mett, J.; Riemenschneider, M.; Grimm, H.S.; Hartmann, T.; Grimm, M.O. Plasmalogens inhibit APP processing by directly affecting ?-secretase activity in Alzheimer’s disease. Sci. World J. 2012, 2012. [CrossRef] [PubMed]
124. Ghosal, K.; Vogt, D.L.; Liang, M.; Shen, Y.; Lamb, B.T.; Pimplikar, S.W. Alzheimer’s disease-like pathological features in transgenic mice expressing the APP intracellular domain. Proc. Natl. Acad. Sci. USA 2009, 106, 18367-18372. [PubMed]
125. Fabelo, N.; Marin, V.; Marin, R.; Moreno, D.; Ferrer, I.; Diaz, M. Altered lipid composition in cortical lipid rafts occurs at early stages of sporadic Alzheimer’s disease and facilitates APP/BACE1 interactions. Neurobiol. Aging 2014, 35, 1801-1812. [CrossRef] [PubMed]
126. Geekiyanage, H.; Upadhye, A.; Chan, C. Inhibition of serine palmitoyltransferase reduces Aß and Tau hyperphosphorylation in a murine model: A safe therapeutic strategy for Alzheimer’s disease. Neurobiol. Aging 2013, 34, 2037-2051. [PubMed]
127. Riemann, D.; Hansen, G.H.; Niels-Christiansen, L.L.; Thorsen, E.; Immerdal, L.; Santos, A.N.; Kehlen, A.; Langner, J.; Danielsen, E.M. Caveolae/lipid rafts in fibroblast-like synoviocytes: Ectopeptidase-rich membrane microdomains. Biochem. J. 2001, 354, 47-55. [CrossRef] [PubMed]
128. Kawarabayashi, T.; Shoji, M.; Younkin, L.H.; Wen-Lang, L.; Dickson, D.W.; Murakami, T.; Matsubara, E.; Abe, K.; Ashe, K.H.; Younkin, S.G. Dimeric amyloid ß protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated Tau accumulation in the Tg2576 mouse model of Alzheimer’s disease. J. Neurosci. 2004, 24, 3801-3809. [CrossRef] [PubMed]
129. Bulloj, A.; Leal, M.C.; Surace, E.I.; Zhang, X.; Xu, H.; Ledesma, M.D.; Castano, E.M.; Morelli, L. Detergent resistant membrane-associated IDE in brain tissue and cultured cells: Relevance to Aß and insulin degradation. Mol. Neurodegener. 2008, 3, 22. [CrossRef] [PubMed]
130. Parkin, E.T.; Watt, N.T.; Hussain, I.; Eckman, E.A.; Eckman, C.B.; Manson, J.C.; Baybutt, H.N.; Turner, A.J.; Hooper, N.M. Cellular prion protein regulates ß-secretase cleavage of the Alzheimer’s amyloid precursor protein. Proc. Natl. Acad. Sci. USA 2007, 104, 11062-11067. [CrossRef] [PubMed]
131. Prybylowski, K.; Chang, K.; Sans, N.; Kan, L.; Vicini, S.; Wenthold, R.J. The synaptic localization of NR2B-containing NMDA receptors is controlled by interactions with PDZ proteins and AP-2. Neuron 2005, 47, 845-857. [CrossRef] [PubMed]
132. Um, J.W.; Strittmatter, S.M. Amyloid-ß induced signaling by cellular prion protein and Fyn kinase in Alzheimer disease. Prion 2013, 7, 37-41. [CrossRef] [PubMed]
133. De Calignon, A.; Polydoro, M.; Suarez-Calvet, M.; William, C.; Adamowicz, D.H.; Kopeikina, K.J.; Pitstick, R.; Sahara, N.; Ashe, K.H.; Carlson, G.A.; et al. Propagation of Tau pathology in a model of early Alzheimer’s disease. Neuron 2012, 73, 685-697. [CrossRef] [PubMed]
134. Ronicke, R.; Mikhaylova, M.; Ronicke, S.; Meinhardt, J.; Schroder, U.H.; Fandrich, M.; Reiser, G.; Kreutz, M.R.; Reymann, K.G. Early neuronal dysfunction by amyloid ß oligomers depends on activation of NR2B-cnotaining NMDA receptors. Neurobiol. Aging 2011, 32, 2219-2228.[CrossRef] [PubMed]
135. Williamson, R.; Usardi, A.; Hanger, D.P.; Anderton, B.H. Membrane-bound ß-amyloid oligomers are recruited into lipid rafts by a fyn-dependent mechanism. FASEB J. 2008, 22, 1552-1559. [CrossRef] [PubMed]
136. Ronicke, R.; Mikhaylova, M.; Ronicke, S.; Meinhardt, J.; Schroder, U.H.; Fandrich, M.; Reiser, G.; Kreutz, M.R.; Reymann, K.G. Early neuronal dysfunction by amyloid ß oligomers depends on activation of NR2B-cnotaining NMDA receptors. Neurobiol. Aging 2011, 32, 2219-2228. [CrossRef] [PubMed]
137. Gimbel, D.A.; Nygaard, H.B.; Coffey, E.E.; Gunther, E.C.; Lauren, J.; Gimbel, Z.A.; Strittmatter, S.M. Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J. Neurosci. 2010, 30, 6367-6374. [CrossRef] [PubMed]
138. Balducci, C.; Beeg, M.; Stravalaci, M.; Bastone, A.; Sclip, A.; Biasini, E.; Tapella, L.; Colombo, L.; Manzoni, C.;Borsello, T.; et al. Synthetic amyloid-ß oligomers impair long-term memory independently of cellular prion protein. Proc. Natl. Acad. Sci. USA 2010, 107, 2295-2300. [CrossRef] [PubMed]
139. Calella, A.M.; Farinelli, M.; Nuvolone, M.; Mirante, O.; Moos, R.; Falsig, J.; Mansuy, I.M.; Aguzzi, A. Prion protein and Aß-related synaptic toxicity impairment. EMBO Mol. Med. 2010, 2, 306-314. [CrossRef] [PubMed]
140. Kudo, W.; Lee, H.P.; Zou, W.Q.; Wang, X.; Perry, G.; Zhu, X.; Smith, M.A.; Petersen, R.B.; Lee, H.G. Cellular prion protein is essential for oligomeric amyloid-ß-induced neuronal cell death. Hum. Mol. Genet. 2012, 21, 1138-1144. [CrossRef] [PubMed]
141. Nicoll, A.J.; Panico, S.; Freir, D.B.; Wright, D.; Terry, C.; Risse, E.; Herron, C.E.; O’Malley, T.; Wadsworth, J.D.; Farrow, M.A.; et al. Amyloid-ß nanotubes are associated with prion protein-dependent synaptotoxicity. Nat. Commun. 2013, 4, 2416. [CrossRef] [PubMed]
142. Hernandez, P.; Lee, G.; Sjoberg, M.; Maccioni, R.B. Tau phosphorylation by Cdk5 and Fyn in response to amyloid peptide Abera (25-35): Involvement of lipid rafts. J. Alzheimers Dis. 2009, 16, 149-156. [PubMed]
143. Sui, Z.; Kovacs, A.D.; Maggirwar, S.B. Recruitment of active glycogen synthase kinase-3 into neuronal lipid rafts. Biochem. Biophys. Res. Commun. 2006, 345, 1643-1648. [CrossRef] [PubMed]
144. Nikolic, M.; Dudek, H.; Kwon, Y.T.; Ramos, Y.F.; Tsai, L.H. The Cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation. Genes Dev. 1996, 10, 816-825. [CrossRef] [PubMed]
145. Kimura, T.; Ishiguro, K.; Hisanaga, S. Physiological and pathological phosphorylation of Tau by Cdk5. Front. Mol. Neurosci. 2014, 7, 65. [CrossRef] [PubMed]
146. Shukla, V.; Skuntz, S.; Pant, H.C. Deregulated Cdk5 activity is involved in inducing Alzheimer’s disease. Arch. Med. Res. 2012, 43, 655-662. [CrossRef] [PubMed]
147. Mazanetz, M.P.; Fischer, P.M. Untangling Tau hyperphosphorylation in drug design for neurodegenerative diseases. Nat. Rev. Drug Discov. 2007, 6, 464-479. [CrossRef] [PubMed]
148. Lee, G.; Thangavel, R.; Sharma, V.M.; Litersky, J.M.; Bhaskar, K.; Fang, S.M.; Do, L.H.; Andreadis, A.; van Hoesen, G.; Ksiezak-Reding, H. Phosphorylation of Tau by fyn: Implications of Alzheimer’s disease.J. Neurosci. 2004, 24, 2304-2312. [CrossRef] [PubMed]
149. Bhaskar, K.; Yen, S.H.; Lee, G. Disease-related modifications in Tau affect the interaction between Fyn and Tau. J. Biol. Chem. 2005, 280, 35119-35125. [CrossRef] [PubMed]
150. Ittner, L.M.; Ke, Y.D.; Delerue, F.; Bi, M.; Gladbach, A.; van Eersel, J.; Wolfing, H.; Chieng, B.C.; Christie, M.J.; Napier, I.A.; et al. Dendritic function of Tau mediates amyloid-ß toxicity in Alzheimer’s disease mouse models. Cell 2010, 142, 387-397. [CrossRef] [PubMed]
151. Usardi, A.; Pooler, A.M.; Seereeram, A.M.; Reynolds, C.H.; Derkinderen, P.; Anderton, B.; Hanger, D.P.; Noble, W.; Williamson, R. Tyrosine phosphorylation of Tau regulates its interactions with Fyn SH2 domains, but not SH3 domains, altering the cellular localization of tau. FEBS J. 2011, 278, 2927-2937. [CrossRef] [PubMed]
152. Liu, F.; Shi, J.; Tranimukai, H.; Gu, J.; Gu, J.; Grundke-Iqbal, I.; Iqbal, K.; Gong, C.X. Reduced O-GlcNAcylation links lower brain glucose metabolism and Tau pathology in Alzheimer’s disease. Brain 2009, 132, 1820-1832. [CrossRef] [PubMed]
153. Velliquette, R.A.; O’Connor, T.; Vassar, R. Energy inhibition elevates ß-secretase levels and activity and is potentially amyloidogenic in APP transgenic mice: Possible early events in Alzheimer’s disease pathogenesis. J. Neurosci. 2005, 25, 10874-10883. [CrossRef] [PubMed]
154. O’Connor, T.; Sadleir, K.R.; Maus, E.; Velliquette, R.A.; Zhao, J.; Cole, S.L.; Eimer, W.A.; Hitt, B.; Bembinster, L.A.; Lammich, S.; et al. Phosphorylation of the translation initiation factor eIF2a increases BACE1 levels and promotes amyloidogenesis. Neuron 2008, 60, 988-1009.[CrossRef] [PubMed]
155. Ankarcrona, M.; Mangialasche, F.; Winblad, B. Rethinking Alzheimer’s disease therapy: Are mitochondria the key? J. Alzheimers Dis. 2010, 20, S579-S590.[PubMed]
156. Jacobsen, K.T.; Iverfeldt, K. O-GlcNAcylation increases non-amyloidogenic processing of the amyloid-ß precursor protein (APP). Biochem. Biophys. Res. Commun. 2011, 404, 882-886. [CrossRef] [PubMed]
157. Liu, K.; Paterson, A.J.; Zhang, F.; McAndrew, J.; Fukuchi, K.; Wyss, J.M.; Peng, L.; Hu, Y.; Kudlow, J.E. Accumulation of protein O-GlcNAc modification inhibits proteasomes in the brain and coincides with neuronal apoptosis in brain areas with high O-GlcNAc metabolism. J. Neurochem. 2004, 89, 1044-1055. [CrossRef] [PubMed]
158. Brister, M.A.; Pandey, A.K.; Bielska, A.A.; Zondlo, N.J. OGlcNAcylation and phosphorylation have opposing structural effects in Tau: Phosphothreonine induces particular conformational order. J. Am. Chem. Soc. 2014, 136, 3803-3816. [CrossRef] [PubMed]
159. Iqbal, K.; Alonso Adel, C.; Chen, S.; Chohan, M.O.; El-Akkad, E.; Gong, C.X.; Khatoon, S.; Li, B.; Liu, F.;Rahman, A.; et al. Tau pathology in Alzheimer disease and other tauopathies. Biochim. Biophys. Acta 2005, 1739, 198-210. [CrossRef] [PubMed]
160. Liu, F.; Iqbal, K.; Grundke-Igbal, I.; Hart, G.W.; Gong, C.X. O-GlcNAcylation regulates phosphorylation ofTau: A mechanism involved in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 2004, 101, 10804-10809. [CrossRef] [PubMed]
161. Tallent, M.K.; Varghis, N.; Skorobogatko, Y.; Hernandez-Cuebas, L.; Whelan, K.; Vocadlo, D.J.; Vosseller, K. In vivo modulation of O-GlcNAc levels regulates hippocampal synaptic plasticity through interplay with phosphorylation. J. Biol. Chem. 2009, 284, 174-181. [CrossRef] [PubMed]
162. Gella, A.; Durany, N. Oxidative stress in Alzheimer disease. Cell Adh. Migr. 2009, 3, 88-93. [CrossRef] [PubMed]
163. Pocernich, C.B.; Butterfield, D.A. Elevation of glutathione as a therapeutic strategy in Alzheimer disease. Biochim. Biophys. Acta 2012, 1822, 625-630. [PubMed]
164. Liu, R.; Choi, J. Age-associated decline in ?-glutamylcysteine synthetase gene expression in rats. Free Radic.Biol. Med. 2000, 28, 566-574. [CrossRef]
165. Saharan, S.; Mandal, P.K. The emerging role of glutathione in Alzheimer’s disease. J. Alzheimers Dis. 2014, 40, 519-529. [PubMed]
166. Lee, M.; Cho, T.; Jantaratnotai, N.; Wang, Y.T.; McGeer, E.; McGeer, P.L. Depletion of GSH in glial cells induces neurotoxicity: Relevance to aging and degenerative neurological diseases. FASEB J. 2010, 24, 2533-2545. [CrossRef] [PubMed]
167. Shen, C.; Chen, Y.; Liu, H.; Zhang, K.; Zhang, T.; Lin, A.; Jing, N. Hydrogen peroxide promotes Aß production through JNK-dependent activation of ?-secretase. J. Biol. Chem. 2008, 283, 17721-17730. [CrossRef] [PubMed]
168. Anantharaman, M.; Tangpong, J.; Keller, J.N.; Murphy, M.P.; Markesbery, W.R.; Kiningham, K.K., St.; Clair, D.K. ß-amyloid mediated nitration of manganese superoxide dismutase: Implication for oxidative stress in a APPNLH/NLH X PS-1P264L/P264L double knock-in mouse model of Alzheimer’s disease. Am. J. Pathol. 2006, 168, 1608-1617. [CrossRef] [PubMed]
169. Lovell, M.A.; Robertson, J.D.; Teesdale, W.J.; Campbell, J.L.; Markesbery, W.R. Copper, iron and zinc in Alzheimer’s disease senile plaques. J. Neurol. Sci. 1998, 158, 47-52. [CrossRef]
170. Atwood, C.S.; Scarpa, R.C.; Huang, X.; Moir, R.D.; Jones, W.D.; Fairlie, D.P.; Tanzi, R.E.; Bush, A.I. Characterization of copper interactions with Alzheimer amyloid ß peptides: Identification of an attomolar-affinity copper binding site on amyloid ß1-42. J. Neurochem. 2000, 75, 1219-1233. [CrossRef] [PubMed]
171. Huang, X.; Cuajungco, M.P.; Atwood, C.S.; Hartshorn, M.A.; Tyndall, J.D.; Hanson, G.R.; Stokes, K.C.; Leopold, M.; Multhaup, G.; Goldstein, L.E.; et al. Cu(II) potentiation of Alzheimer Aß neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J. Biol. Chem. 1999, 274, 37111-37116. [CrossRef] [PubMed]
172. Al-Hilaly, Y.K.; Williams, T.L.; Stewart-Parker, M.; Ford, L.; Skaria, E.; Cole, M.; Bucher, W.G.; Morris, K.L.; Sada, A.A.; Thorpe, J.R.; et al. A central role for dityrosine crosslinking of amyloid-ß in Alzheimer’s disease. Acta Neuropathol. Commun. 2013, 1, 83. [CrossRef] [PubMed]
173. Hensley, K.; Maidt, M.L.; Yu, Z.; Sang, H.; Markesbery, W.R.; Floyd, R.A. Electrochemical analysis of protein nitrotyrosine and dityrosine in the Alzheimer brain indicates region-specific accumulation. J. Neurosci. 1998, 18, 8126-8132. [PubMed]
174. Cuajungco, M.P.; Goldstein, L.E.; Nunomura, A.; Smith, M.A.; Lim, J.T.; Atwood, C.S.; Huang, X.; Farrag, Y.W.; Perry, G.; Bush, A.I. Evidence that the ß-amyloid plaques of Alzheimer’s disease represent the redox-silencing and entombment of Aß by zinc. J. Biol. Chem. 2000, 275, 19439-19442. [CrossRef] [PubMed]
175. Craddock, T.J.; Tuszynski, J.A.; Chopra, D.; Casey, N.; Goldstein, L.E.; Hameroff, S.R.; Tanzi, R.E. The zinc dyshoemostasis hypothesis of Alzheimer’s disease. PLoS ONE 2012, 7, e33552. [CrossRef] [PubMed]
176. Yan, S.D.; Chen, X.; Fu, J.; Chen, M.; Zhu, H.; Roher, A.; Slattery, T.; Zhao, L.; Nagashima, M.; Morser, J.; et al. RAGE and amyloid-ß peptide neurotoxicity in Alzheimer’s disease. Nature 1996, 382, 685-691. [CrossRef] [PubMed]
177. Bierhaus, A.; Humpert, P.M.; Morcos, M.; Wendt, T.; Chavakis, T.; Arnold, B.; Stern, D.M.; Nawroth, P.P. Understanding RAGE, the receptor for advanced glycation end products. J. Mol. Med. 2005, 83, 876-886. [CrossRef] [PubMed]
178. Srikanth, V.; Maczurek, A.; Phan, T.; Steele, M.; Westcott, B.; Juskiw, D.; Munch, G. Advanced glycation endproducts and their receptor RAGE in Alzheimer’s disease. Neurobiol. Aging 2011, 32, 763-777. [CrossRef] [PubMed]
179. Valente, T.; Gella, A.; Fernandez-Busquets, X.; Unzeta, M.; Durany, N. Immunohistochemical analysis ofhuman brain suggests pathological synergism of Alzheimer’s disease and diabetes mellitus. Neurobiol. Dis. 2010, 37, 67-76. [CrossRef] [PubMed]
180. Cho, H.J.; Son, S.M.; Jin, S.M.; Hong, H.S.; Shin, D.H.; Kim, S.J.; Huh, K.; Mook-Jung, I. RAGE regulates BACE1 and Aß generation via NFAT1 activation in Alzheimer’s disease animal model. FASEB J. 2009, 23, 2639-2649. [CrossRef] [PubMed]
181. Yan, S.D.; Bierhaus, A.; Nawroth, P.P.; Stern, D.M. RAGE and Alzheimer’s disease: A progression factor foramyloid-ß-induced cellular perturbation? J. Alzheimers Dis. 2009, 16, 833-843. [PubMed]
182. Martel, C.L.; Mackic, J.B.; McComb, J.G.; Ghiso, J.; Zlokovic, B.V. Blood-brain barrier uptake of the 40 and 42 amino acid sequences of circulating Alzheimer’s amyloid ß in guinea pigs. Neurosci. Lett. 1996, 206, 157-160. [CrossRef]
183. Deane, R.; du Yan, S.; Submamaryan, R.K.; LaRue, B.; Jovanovic, S.; Hogg, E.; Welch, D.; Manness, L.; Lin, C.; Yu, J.; et al. RAGE mediates amyloid-ß peptide transport across the blood-brain barrier and accumlation in brain. Nat. Med. 2003, 9, 907-913. [CrossRef] [PubMed]
184. Manolopoulos, K.N.; Klotz, L.O.; Korsten, P.; Bornstein, S.R.; Barthel, A. Linking Alzheimer’s disease to insulin resistance: The FoxO response to oxidative stress. Mol. Psychiatry 2010, 15, 1046-1052. [CrossRef] [PubMed]
185. Hardas, S.S.; Sultana, R.; Clark, A.M.; Beckett, T.L.; Szweda, L.I.; Murphy, M.P.; Butterfield, D.A. Oxidative modification of lipoic acid by HNE in Alzheimer disease brain. Redox Biol. 2013, 1, 80-85. [CrossRef] [PubMed]
186. Siegel, S.J.; Bieschke, J.; Powers, E.T.; Kelly, J.W. The oxidative stress metabolite 4-hydroxynonenal promotes Alzheimer protofibril formation. Biochemistry 2007, 46, 1503-1510. [CrossRef] [PubMed]
187. Markesbery, W.R.; Lovell, M.A. Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer’s disease. Neurobiol. Aging 1998, 19, 33-36. [CrossRef]
188. Schulingkamp, R.J.; Pagano, T.C.; Hung, D.; Raffa, R.B. Insulin receptors and insulin action in the brain:Review and clinical implications. Neurosci. Biobehav. Rev. 2000, 24, 855-872. [CrossRef]
189. Dore, S.; Kar, S.; Quirion, R. Insulin-like growth factor I protects and rescues hippocampal neurons against ß-amyloid- and human amylin-induced toxicity. Proc. Natl. Acad. Sci. USA 1997, 94, 4772-4777. [CrossRef] [PubMed]
190. Fernandez, A.M.; Torres-Aleman, I. The many faces of insulin-like peptide signalling in the brain. Nat. Rev. Neurosci. 2012, 13, 225-239. [CrossRef] [PubMed]
191. Wozniak, M.; Rydzewski, B.; Baker, S.P.; Raizada, M.K. The cellular and physiological actions of insulin in the central nervous system. Neurochem. Int. 1993, 22, 1-10. [CrossRef]
192. Sesti, G.; Federici, M.; Hribal, M.L.; Lauro, D.; Sbraccia, P.; Lauro, R. Defects of the isnulin receptor substrate (IRS) system in human metabolic disorders. FASEB J. 2001, 15, 2099-2111. [CrossRef] [PubMed]
193. White, M.F. Insulin signaling in health and disease. Science 2003, 302, 1710-1711. [CrossRef] [PubMed]
194. Schubert, M.; Brazil, D.P.; Burks, D.J.; Kushner, J.A.; Ye, J.; Flint, C.L.; Farhang-Fallah, J.; Dikkes, P.;Warot, X.M.; Rio, C.; et al. Insulin receptor substrate-2 deficiency impairs brain growth and promotes Tau phosphorylation. J. Neurosci. 2003, 23, 7084-7092. [PubMed]
195. Schubert, M.; Gautam, D.; Surjo, D.; Ueki, K.; Baudler, S.; Schubert, D.; Kondo, T.; Alber, J.; Galldiks, N.;Kustermann, E.; et al. Role for neuronal insulin resistance in neurodegenerative diseases. Proc. Natl. Acad. Sci. USA 2004, 101, 3100-3105. [CrossRef] [PubMed]
196. Cheng, C.M.; Tseng, V.; Wang, J.; Wang, D.; Matyakhina, L.; Bondy, C.A. Tau is hyperphosphorylated in the insulin-like growth factor-I null brain. Endocrinology 2005, 146, 5086-5091. [CrossRef] [PubMed]
197. Killick, R.; Scales, G.; Leroy, K.; Causevic, M.; Hooper, C.; Irvine, E.E.; Choudhury, A.I.; Drinkwater, L.; Kerr, F.; Al-Qassab, H.; et al. Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice. Biochem. Biophys. Res. Commun. 2009, 386, 257-262. [CrossRef] [PubMed]
198. Moloney, A.M.; Griffin, R.J.; Timmons, S.; O’Connor, R.; Ravid, R.; O’Neil, C. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol. Aging 2010, 31, 224-243. [CrossRef] [PubMed]
199. Cross, D.A.; Alessi, D.R.; Cohen, P.; Andjelkovich, M.; Hemmings, B.A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995, 378, 785-789. [CrossRef] [PubMed]
200. Alessi, D.R.; Cohen, P. Mechanism of activation and function of protein kinase B. Curr. Opin. Genet. Dev.1998, 8, 55-62. [CrossRef]
201. Frolich, L.; Blum-Degen, D.; Bernstein, H.G.; Engelsberger, B.S.; Humrich, J.; Laufer, S.; Muschner, D.; Thalheimer, A.; Turk, A.; Hoyer, S.; et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J. Neural Transm. 1998, 105, 423-438.
202. Hotamisligil, G.S.; Peraldi, P.; Budavari, A.; Ellis, R.; White, M.F.; Spiegelman, B.M. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-a- and obesity-induced insulin resistance. Science 1996, 271, 665-668. [CrossRef] [PubMed]
203. Aguirre, V.; Werner, E.D.; Giraud, J.; Lee, Y.H.; Shoelson, S.E.; White, M.F. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J. Biol. Chem. 2002, 277, 1531-1537. [CrossRef] [PubMed]
204. Paz, K.; Hemi, R.; LeRoith, D.; Karasik, A.; Elhanany, E.; Kanety, H.; Zick, Y. A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin and impairs their ability to undergo insulin-induced tyrosine phosphorylation. J. Biol. Chem. 1997, 272, 29911-29918. [CrossRef] [PubMed]
205. De Felice, F.G.; Lourenco, M.V.; Ferreira, S.T. How does brain insulin resistance develop in Alzheimer’s disease? Alzheimers Dement. 2014, 10, S26-S32. [CrossRef] [PubMed]
206. Butterfield, D.A.; di Domenico, F.; Barone, E. Elevated risk of type 2 diabetes for development of Alzheimer disease: A key role for oxidative stress in brain. Biochim. Biophys. Acta 2014, 1842, 1693-1706. [CrossRef] [PubMed]
207. Dou, J.T.; Chen, M.; Dufour, F.; Alkon, D.L.; Zhao, W.Q. Insulin receptor signaling in long-term memory consolidation following spatial learning. Learn. Mem. 2005, 12, 646-655. [CrossRef] [PubMed]
208. Cole, G.M.; Frautschy, S.A. The role of insulin and neurotrophic factor signaling in brain aging and Alzheimer’s disease. Exp. Gerontol. 2007, 42, 10-21. [CrossRef] [PubMed]
209. Zhao, W.Q.; Lacor, P.N.; Chen, H.; Lambert, M.P.; Quon, M.J.; Krafft, G.A.; Klein, W.L. Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomeric Aß. J. Biol. Chem. 2009, 284, 18742-18753. [CrossRef] [PubMed]
210. Vekrellis, K.; Ye, Z.; Qiu, W.Q.; Walsh, D.; Hartley, D.; Chesneau, V.; Rosner, M.R.; Selkoe, D.J. Neurons regulate extracellular levels of amyloid ß-protein via proteolysis by insulin-degrading enzyme. J. Neurosci. 2000, 20, 1657-1665. [PubMed]
211. Zhao, L.; Teter, B.; Morihara, T.; Lim, G.P.; Ambegaokar, S.S.; Ubeda, O.J.; Frautschy, S.A.; Cole, G.M. Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: Implications for Alzheimer’s disease intervention. J. Neurosci. 2004, 24, 11120-11126. [CrossRef] [PubMed]
212. Reger, M.A.; Watson, G.S.; Green, P.S.; Baker, L.D.; Cholerton, B.; Fishel, M.A.; Plymate, S.R.; Cherrier, M.M.; Schellenberg, G.D.; Frey, W.H., II; et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-ß in memory-impaired older adults. J. Alzheimers Dis. 2008, 13, 323-331. [PubMed]
213. Cook, D.G.; Leverenz, J.B.; McMillan, P.J.; Kulstad, J.J.; Ericksen, S.; Roth, R.A.; Schellenberg, G.D.; Jin, L.W.; Kovacina, K.S.; Craft, S. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer’s disease is associated with the apolipoprotein E-epsiron4 allele. Am. J. Pathol. 2003, 162, 313-319. [CrossRef]
214. Pelvig, D.P.; Pakkenberg, H.; Stark, A.K.; Pakkenberg, B. Neocortical glial cell numbers in human brains. Neurobiol. Aging 2008, 29, 1754-1762. [CrossRef] [PubMed]
215. Derecki, N.C.; Katzmarski, N.; Kipnis, J.; Meyer-Luehmann, M. Microglia as a critical player in both developmental and late-life CNS pathogenesis. Acta Neuropathol. 2014, 128, 333-345. [CrossRef] [PubMed]
216. Ekdahl, C.T.; Claasen, J.H.; Bonde, S.; Kokaia, Z.; Lindvall, O. Inflammation is detrimental for neurogenesis in adult brain. Proc. Natl. Acad. Sci. USA 2003, 100, 13632-13637. [CrossRef] [PubMed]
217. Monje, M.L.; Toda, H.; Palmer, T.D. Inflammatory blockade restores adult hippocampal neurogenesis. Science 2003, 302, 1760-1765. [CrossRef] [PubMed]
218. Ziv, Y.; Ron, N.; Butovsky, O.; Landa, G.; Greenberg, N.; Cohen, H.; Kipnis, J.; Schwartz, M. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat. Neurosci. 2006, 9, 268-275. [CrossRef] [PubMed]
219. Li, Y.; Liu, L.; Barger, S.W.; Griffin, W.S. Interleukin-1 mediates pathological effects of microglia on Tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J. Neurosci. 2003, 23, 1605-1611. [PubMed]
220. Harrison, J.K.; Jiang, Y.; Chen, S.; Xia, Y.; Maciejewski, D.; McNamara, R.K.; Streit, W.J.; Salafranca, M.N.; Adhikari, S.; Thompson, D.A.; et al. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc. Natl. Acad. Sci. USA 1998, 95, 10896-10901. [CrossRef] [PubMed]
221. Hatori, H.; Nagai, A.; Heisel, R.; Ryu, J.K.; Kim, S.U. Fractalkine and fractalkine receptors in human neurons and glial cells. J. Neurosci. Res. 2002, 69, 418-426. [CrossRef] [PubMed]
222. Re, D.B.; Przedborski, S. Fractalkine: Moving from chemotaxis to neuroprotection. Nat. Neurosci. 2006, 9, 859-861. [PubMed]
223. Lyons, A.; Lynch, A.M.; Downer, E.J.; Hanley, R.; O’Sullivan, J.B.; Smith, A.; Lynch, M.A. Fractalkine-induced activation of the phosphatidylinositol-3 kinase pathway attenuates microglial activation in vivo and in vitro. J. Neurochem. 2009, 110, 1547-1556. [CrossRef] [PubMed]
224. Deiva, K.; Geeraerts, T.; Salim, H.; Leclerc, P.; Hery, C.; Hugel, B.; Freyssinet, J.M.; Tardieu, M. Fractalkine reduces N-methyl-D-aspartate-induced calcium flux and apoptosis in human neurons through extracellular signal-regulated kinase activation. Eur. J. Neurosci. 2004, 20, 3222-3232. [CrossRef] [PubMed]
225. Limatola, C.; Lauro, C.; Catalano, M.; Ciotti, M.T.; Bertollini, C.; di Angelantonio, S.; Ragozzino, D.; Eusebi, F. Chemokine CX3CL1 protects rat hippocampal neurons against glutamate-mediated excitotoxicity. J. Neuroimmunol. 2005, 166, 19-28. [CrossRef] [PubMed]
226. Kim, T.S.; Lim, H.K.; Lee, J.Y.; Kim, D.J.; Park, S.; Lee, C.; Lee, C.U. Changes in the levels of plasma soluble fractalkine in patients with mild cognitive impairment and Alzheimer’s disease. Neurosci. Lett. 2008, 436, 196-200. [CrossRef] [PubMed]
227. Cho, S.H.; Sun, B.; Zhou, Y.; Kauppinen, T.M.; Halabisky, B.; Wes, P.; Ransohoff, R.M.; Gan, L. CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease. J. Biol. Chem. 2011, 286, 32713-32722. [CrossRef] [PubMed]
228. Lyons, A.; Downer, E.J.; Crotty, S.; Nolan, Y.M.; Mills, K.H.; Lynch, M.A. CD200 ligand receptor interaction modulates microglial activation in vivo and in vitro: A role for IL-4. J. Neurosci. 2007, 27, 8309-8313. [CrossRef] [PubMed]
229. Hernangomez, M.; Carrillo-Salinas, F.J.; Mecha, M.; Correa, F.; Mestre, L.; Loria, F.; Feliu, A.; Docagne, F.; Guaza, C. Brain innate immunity in the regulation of neuroinflammation: Therapeutic strategies by modulating CD200-CD200R interaction involve the cannabinoid system. Curr. Pharm. Des. 2014, 20,4707-4722. [CrossRef] [PubMed]
230. Cox, F.F.; Carney, D.; Miller, A.M.; Lynch, M.A. CD200 fusion protein decreases microglial activation in the hippocampus of aged rats. Brain Behav. Immun. 2012, 26, 789-796. [CrossRef] [PubMed]
231. Frank, M.G.; Barrientos, R.M.; Biedenkapp, J.C.; Rudy, J.W.; Watkins, L.R.; Maier, S.F. mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging. Neurobiol. Aging 2006, 27, 717-722. [CrossRef] [PubMed]
232. Walker, D.G.; Dalsing-Hernandez, J.E.; Campbell, N.A.; Lue, L.F. Decreased expression of CD200 and CD200 receptor in Alzheimer’s disease: A potential mechanism leading to chronic inflammation. Exp. Neurol. 2009, 215, 5-19. [CrossRef] [PubMed]
233. Costello, D.A.; Lyons, A.; Denieffe, S.; Browne, T.C.; Cox, F.F.; Lynch, M.A. Long term potentiation is impaired in membrane glycoprotein CD200-deficient mice: A role for Toll-like receptor activation. J. Biol. Chem. 2011, 286, 34722-34732. [CrossRef] [PubMed]
234. Okun, E.; Mattson, M.P.; Arumugam, T.V. Involvement of Fc receptors in disorders of the central nervoussystem. Neuromol. Med. 2010, 12, 164-178. [CrossRef] [PubMed]
235. Guilliams, M.; Bruhns, P.; Saeys, Y.; Hammad, H.; Lambrecht, B.N. The function of Fc? receptors in dendritic cells and macrophages. Nat. Rev. Immunol. 2014, 14, 94-108. [CrossRef] [PubMed]
236. Gaikwad, S.; Larionov, S.; Wang, Y.; Dannenberg, H.; Matozaki, T.; Monsonego, A.; Thal, D.R.; Neumann, H. Signal regulatory protein-ß1: A microglial modulator of phagocytosis in Alzheimer’s disease. Am. J. Pathol. 2009, 175, 2528-2539. [CrossRef] [PubMed]
237. Doens, D.; Fernandez, P.L. Microglia receptors and their implications in the response to amyloid ß for Alzheimer’s disease pathogenesis. J. Neuroinflamm. 2014, 11, 48. [CrossRef] [PubMed]
238. Qiu, W.Q.; Ye, Z.; Kholodenko, D.; Seubert, P.; Selkoe, D.J. Degradation of amyloid ß-protein by a metalloprotease secreted by microglia and other neural and non-neural cells. J. Biol. Chem. 1997, 272, 6641-6646. [CrossRef] [PubMed]
239. Qiu, W.Q.; Walsh, D.M.; Ye, Z.; Vekrellis, K.; Zhang, J.; Podlisny, M.B.; Rosner, M.R.; Safavi, A.; Hersh, L.B.; Selkoe, D.J. Insulin-degrading enzyme regulates extracellular levels of amyloid ß-protein by degradation. J. Biol. Chem. 1998, 273, 32730-32738. [CrossRef] [PubMed]
240. Carson, J.A.; Turner, A.J. ß-amyloid catabolism: Roles for neprilysin (NEP) and other metallopeptidases? J. Neurochem. 2002, 81, 1-8. [CrossRef] [PubMed]
241. Sakamoto, M.; Miyamoto, K.; Wu, Z.; Nakanishi, H. Possible involvement of cathepsin B released by microglia in methylmercury-induced cerebellar pathological changes in the adult rat. Neurosci. Lett. 2008, 442, 292-296. [CrossRef] [PubMed]
242. Mosher, K.I.; Wyss-Coray, T. Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem. Pharmacol. 2014, 88, 594-604. [CrossRef] [PubMed]
243. Lucin, K.M.; O’Brien, C.E.; Bieri, G.; Czirr, E.; Mosher, K.I.; Abbey, R.J.; Mastroeni, D.F.; Rogers, J.; Spencer, B.; Masliah, E.; et al. Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer’s disease. Neuron 2013, 79, 873-886. [CrossRef] [PubMed]
244. Lamkanfi, M.; Vande Walle, L.; Kanneganti, T.D. Deregulated inflammasome signaling in disease. Immunol. Rev. 2011, 243, 163-173. [CrossRef] [PubMed]
245. Koenigsknecht-Talboo, J.; Landreth, G.E. Microglial phagocytosis induced by fibrillar ß-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J. Neurosci. 2005, 25, 8240-8249. [CrossRef] [PubMed]
246. Heneka, M.T.; Kummer, M.P.; Stutz, A.; Delekate, A.; Schwartz, S.; Vieira-Saecker, A.; Griep, A.; Axt, D.; Remus, A.; Tzeng, T.; et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 2013, 493, 674-678. [CrossRef] [PubMed]
247. Nagelhus, E.A.; Amiry-Moghaddam, M.; Bergersen, L.H.; Bjaalie, J.G.; Eriksson, J.; Gundersen, V.; Leergaard, T.B.; Morth, J.P.; Storm-Mathisen, J.; Trop, R.; et al. The glia doctorine: Addressing the role of glial cells in healthy brain ageing. Mech. Ageing Dev. 2013, 134, 449-459. [CrossRef] [PubMed]
248. Choi, S.S.; Lee, H.J.; Lim, I.; Satoh, J.; Kim, S.U. Human astrocytes: Secretome profiles of cytokines and chemokines. PLoS ONE 2014, 9, e92325. [CrossRef] [PubMed]
249. Sykova, E. Glial diffusion barriers during aging and pathological states. Prog. Brain Res. 2001, 132, 339-363.[PubMed]
250. Vargova, L.; Sykova, E. Astrocytes and extracellular matrix in extrasynaptic volume transmission. Philos. Trans. R. Soc. Lond. B 2014, 369. [CrossRef] [PubMed]
251. Swanson, R.A.; Ying, W.; Kauppinen, T.M. Astrocyte influences on ischemic neuronal death. Curr. Mol. Med. 2004, 4, 193-205. [CrossRef] [PubMed]
252. Pekny, M.; Wilhelmsson, U.; Bogestal, Y.R.; Pekna, M. The role of astrocytes and complement system in neural plasticity. Int. Rev. Neurobiol. 2007, 82, 95-111. [PubMed]
253. Apelt, J.; Schliebs, R. ß-amyloid-induced glial expression of both pro- and anti-inflammatory cytokines in cerebral cortex of aged transgenic Tg2576 mice with Alzheimer plaque pathology. Brain Res. 2001, 894, 21-30. [CrossRef]
254. Papadopoulos, M.C.; Verkman, A.S. Aquaporin water channels in the nervous system. Nat. Rev. Neurosci. 2013, 14, 265-277. [CrossRef] [PubMed]
255. Butterfield, D.A.; Pocernich, C.B. The glutamatergic system and Alzheimer’s disease: Therapeutic implications. CNS Drugs 2003, 17, 641-652. [CrossRef] [PubMed]
256. Lauderback, C.M.; Hackett, J.M.; Huang, F.F.; Keller, J.N.; Szweda, L.I.; Markesbery, W.R.; Butterfield, D.A. The glial glutamate transporter, GLT-1, is oxidatively modified by 4-hydroxy-2-nonenal in the Alzheimer’s disease brain: The role of Aß1-42. J. Neurochem. 2001, 78, 413-416. [CrossRef] [PubMed]
257. Masliah, E.; Alford, M.; de Teresa, R.; Mallory, M.; Hansen, L. Deficient glutamate transport is associated with neurodegeneration in Alzheimer’s disease. Ann. Neurol. 1996, 40, 759-766. [CrossRef] [PubMed]
258. Korn, T.; Magnus, T.; Jung, S. Autoantigen specific T cells inhibit glutamate uptake in astrocytes by decreasing expression of astrocytic glutamate transporter GLAST: A mechanism mediated by tumor necrosis factor-a. FASEB J. 2005, 19, 1878-1880. [CrossRef] [PubMed]
259. Zou, J.; Wang, Y.X.; Dou, F.F.; Lu, H.Z.; Ma, Z.W.; Lu, P.H.; Xu, X.M. Glutamine synthetase down-regulation reduces astrocyte protection against glutamate excitotoxicity to neurons. Neurochem. Int. 2010, 56, 577-584. [CrossRef] [PubMed]
260. Olabarria, M.; Noristani, H.N.; Verkhratsky, A.; Rodriguez, J.J. Age-dependent decrease in glutamine synthetase expression in the hippocampal astroglia of the triple transgenic Alzheimer’s disease mouse model: Mechanism of deficient glutamategic transmission? Mol. Neurodegener. 2011, 6, 55. [CrossRef] [PubMed]
261. Kulijewicz-Nawrot, M.; Verkhratsky, A.; Chvatal, A.; Sykova, E.; Rodriguez, J.J. Astrocytic cytoskeletal atrophy in the medial prefrontal cortex of a triple transgenic mouse model of Alzheimer’s disease. J. Anat. 2012, 221, 252-262. [CrossRef] [PubMed]
262. Oberstein, T.J.; Spitzer, P.; Klafki, H.W.; Linning, P.; Neff, F.; Knolker, H.J.; Lewczuk, P.; Wiltfang, J.; Kornhuber, J.; Maler, J.M. Astrocytes and microglia but not neurons preferentially generate N-terminally truncated Aß peptides. Neurobiol. Dis. 2015, 73, 24-35.
263. Yin, K.J.; Cirrito, J.R.; Yan, P.; Hu, X.; Xiao, Q.; Pan, X.; Bateman, R.; Song, H.; Hsu, F.F.; Turk, J.; et al. Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-ß peptide catabolism. J. Neurosci. 2006, 26, 10939-10948. [CrossRef] [PubMed]
264. Kanemitsu, H.; Tomiyama, T.; Mori, H. Human neprilysin is capable of degrading amyloid ß peptide not only in the monomeric form but also the pathological oligomeric form. Neurosci. Lett. 2003, 350, 113-116. [CrossRef]
265. Eckman, E.A.; Eckman, C.B. Aß-degrading enzymes: Modulators of Alzheimer’s disease pathogenesis and targets for therapeutic intervention. Biochem. Soc. Trans. 2005, 33, 1101-1105. [CrossRef] [PubMed]
266. Elshourbagy, N.A.; Liao, W.S.; Mahley, R.W.; Taylor, J.M. Apolipoprotein E mRNA is abundant in the brain and adrenals, as well as in the liver, and is present in other peripheral tissues of rats and marmosets. Proc. Natl. Acad. Sci. USA 1985, 82, 203-207. [CrossRef] [PubMed]
267. Pitas, R.E.; Boyles, J.K.; Lee, S.H.; Foss, D.; Mahley, R.W. Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim. Biophys. Acta 1987, 917, 148-161. [CrossRef]
268. Nakai, M.; Kawamata, T.; Taniguchi, T.; Maeda, K.; Tanaka, C. Expression of apolipoprotein E mRNA in rat microglia. Neurosci. Lett. 1996, 211, 41-44. [CrossRef]
269. Hatters, D.M.; Peters-Libeu, C.A.; Weisgraber, K.H. Apolipoprotein E structure: Insights into function. Trends Biochem. Sci. 2006, 31, 445-454. [CrossRef] [PubMed]
270. Kanekiyo, T.; Xu, H.; Bu, G. ApoE and Aß in Alzheimer’s disease: Accidental encounters or partners? Neuron 2014, 81, 740-754. [CrossRef] [PubMed]
271. Holtzman, D.M.; Herz, J.; Bu, G. Apolipoprotein E and apolipoprotein E receptors: Normal biology and role in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2012, 2. [CrossRef] [PubMed]
272. Basak, J.M.; Verghese, P.B.; Yoon, H.; Kim, J.; Hotzman, D.M. Low-density lipoprotein receptor represent an apolipoprotein E-independent pathway of Aß uptake and degradation by astrocytes. J. Biol. Chem. 2012, 287, 13959-13971. [CrossRef] [PubMed]
273. Myung, N.H.; Zhu, X.; Kruman, I.I.; Castellani, R.J.; Petersen, R.B.; Siedlak, S.L.; Perry, G.; Smith, M.A.; Lee, H.G. Evidence of DNA damage in Alzheimer disease: Phosphorylation of histone H2AX in astrocytes. Age 2008, 30, 209-215. [CrossRef] [PubMed]
274. Bhat, R.; Crowe, E.P.; Bitto, A.; Moh, M.; Katsetos, C.D.; Garcia, F.U.; Johnson, F.B.; Trojanowski, J.Q.; Sell, C.; Torres, C. Astrocyte senescence as a component of Alzheimer’s disease. PLoS ONE 2012, 7, e45069. [CrossRef] [PubMed]
275. Oakley, H.; Cole, S.L.; Logan, S.; Maus, E.; Shao, P.; Craft, J.; Guillozet-Bongaarts, A.; Ohno, M.; Disterhoft, J.; van Eldik, L.; et al. Intraneuronal ß-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: Potential factors in amyloid plaque formation. J. Neurosci. 2006, 26, 10129-10140. [CrossRef] [PubMed]
276. Oddo, S.; Caccamo, A.; Kitazawa, M.; Tseng, B.P.; LaFerla, F.M. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol. Aging 2003, 24, 1063-1070. [CrossRef] [PubMed]
277. Rohn, T.T.; Vyas, V.; Hernandez-Estrada, T.; Nichol, K.E.; Christie, L.A.; Head, E. Lack of pathology in a triple transgenic mouse model of Alzheimer’s disease after overexpression of the anti-apoptotic protein Bcl-2. J. Neurosci. 2008, 28, 3051-3059. [CrossRef] [PubMed]
278. Akiyama, H.; Barger, S.; Barnum, S.; Bradt, B.; Bauer, J.; Cole, G.M.; Cooper, N.R.; Eikelenboom, P.; Emmerling, M.; Fiebich, B.L.; et al. Inflammation and Alzheimer’s disease. Neurobiol. Aging 2000, 21, 383-421. [CrossRef]
279. Montkowski, A.; Poetting, M.; Mederer, A.; Holsboer, F. Behavioural performance in three substrains of mouse strain 129. Brain Res. 1997, 762, 12-18. [CrossRef]
280. Balogh, S.A.; McDowell, C.S.; Stavnezer, A.J.; Denenberg, V.H. A behavioral and neuroanatomical assessment of an inbred substrain of 129 mice with behavioral comparisons to C57BL/6J mice. Brain Res.1999, 836, 38-48. [CrossRef]
281. Gerlai, R. Gene-targeting studies of mammalian behavior: Is it the mutation or the background genotype? Trends Neurosci. 1996, 19, 177-181. [CrossRef]
282. Wolfer, D.P.; Muller, U.; Stagliar, M.; Lipp, H.P. Assessing the effects of the 129/Sc genetic background on swimming navigation learning in transgenic mutants: A study using mice with a modified ß-amyloid precursor protein gene. Brain Res. 1997, 771, 1-13. [CrossRef]
283. Takeda, T. Senescence-accelerated mouse (SAM) with special references to neurodegeneration models, SAMP8 and SAMP10 mice. Neurochem. Res. 2009, 34, 639-659. [CrossRef] [PubMed]
284. Ma, Q.; Qiang, J.; Gu, P.; Wang, Y.; Geng, Y.; Wang, M. Age-related autophagy alterations in the brain of senescence accelerated mouse prone 8 (SAMP8) mice. Exp. Gerontol. 2011, 46, 533-541. [CrossRef] [PubMed]
285. Alvarez-Garcia, O.; Vega-Naredo, I.; Sierra, V.; Caballero, B.; Tomas-Zapico, C.; Camins, A.; Garcia, J.J.; Pallas, M.; Coto-Montes, A. Elevated oxidative stress in the brain of senescence-accelerated mice at 5 months of age. Biogerontology 2006, 7, 43-52. [CrossRef] [PubMed]
286. Morley, J.E.; Farr, S.A.; Kumar, V.B.; Armbrecht, H.J. The SAMP8 mouse: A model to develop therapeutic interventions for Alzheimer’s disease. Curr. Pharm. Des. 2012, 18, 1123-1130. [CrossRef] [PubMed]
287. Li, M.; Inaba, M.; Guo, K.; Abraham, N.G.; Ikehara, S. Amelioration of cognitive ability in senescence-accelerated mouse prone 8 (SAMP8) by intra-bone marrow-bone marrow transplantation. Neurosci. Lett. 2009, 465, 36-40. [CrossRef] [PubMed]
288. Chouliaras, L.; Rutten, B.P.; Kenis, G.; Peerbooms, O.; Visser, P.J.; Verhey, F.; van Os, J.; Steinbusch, H.W.; van den Hove, D.L. Epigenetic regulation in the pathophysiology of Alzheimer’s disease. Prog. Neurobiol. 2010, 90, 498-510. [CrossRef] [PubMed]
289. Lee, H.J.; Lee, J.K.; Lee, H.; Carter, J.E.; Chang, J.W.; Oh, W.; Yang, Y.S.; Suh, J.G.; Lee, B.H.; Jin, H.K.; et al. Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer’s disease mouse model through modulation of neuroinflammation. Neurobiol. Aging 2012, 33, 588-602. [CrossRef] [PubMed]
290. Park, H.J.; Shin, J.Y.; Lee, B.R.; Kim, H.O.; Lee, P.H. Mesenchymal stem cells augment neurogenesis in the subventricular zone and enhance differentiation of neural precursor cells into dopaminergic neurons in the substantia nigra of a parkinsonian model. Cell Transpl. 2012, 21, 1629-1640. [CrossRef] [PubMed]
291. Martinez-Morales, P.L.; Revilla, A.; Ocana, I.; Gonzalez, C.; Sainz, P.; McGuire, D.; Liste, I. Progress in stem cell therapy for major human neurological disorders. Stem Cell Rev. 2013, 9, 685-699. [CrossRef] [PubMed]
292. Forostyak, S.; Homola, A.; Turnovcova, K.; Svitil, P.; Jendelova, P.; Sykova, E. Intrathecal delivery of mesenchymal stromal cells protects the structure of altered perineuronal nets in SOD1 rats and amends the course of ALS. Stem Cells 2014, 32, 3163-3172. [CrossRef] [PubMed]
293. Mazzini, L.; Vercelli, A.; Ferrero, I.; Boido, M.; Cantello, R.; Fagioli, F. Transplantation of mesenchymal stem cells in ALS. Prog. Brain Res. 2012, 201, 333-359. [PubMed]
294. Hayashi, T.; Wakao, S.; Kitada, M.; Ose, T.; Watabe, H.; Kuroda, Y.; Mitsunaga, K.; Matsuse, D.; Shigemoto, T.; Ito, A.; et al. Autologous mesenchymal stem cell-derived dopaminergic neurons function in parkinsonian macaques. J. Clin. Investig. 2013, 123, 272-284. [CrossRef] [PubMed]
295. Glavaski-Joksimovic, A.; Bohn, M.C. Mesenchymal stem cells and neuroregeneration in Parkinson’s disease. Exp. Neurol. 2013, 247, 25-38. [CrossRef] [PubMed]
296. Kern, S.; Eichler, H.; Stoeve, J.; Kluter, H.; Bieback, K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2006, 24, 1294-1301. [CrossRef] [PubMed]
297. Kassem, M. Abdallah, B.M. Human bone-marrow-derived mesenchymal stem cells: Biological characteristics and potential role in therapy of degenerative diseases. Cell Tissue Res. 2008, 331, 157-163. [CrossRef] [PubMed]
298. Fukuchi, Y.; Nakajima, H.; Sugiyama, D.; Hirose, I.; Kitamura, T.; Tsuji, K. Human placenta-derived cells have mesenchymal stem/progenitor cell potential. Stem Cells 2004, 22, 649-658. [CrossRef] [PubMed]
299. Wyse, R.D.; Dunbar, G.L.; Rossignol, J. Use of genetically modified mesenchymal stem cells to treat neurodegenerative diseases. Int. J. Mol. Sci. 2014, 15, 1719-1745.
300. Harting, M.T.; Jimenez, F.; Xue, H.; Fischer, U.M.; Baumgartner, J.; Dash, P.K.; Cox, C.S. Intravenous mesenchymal stem cell therapy for traumatic brain injury. J. Neurosurg. 2009, 110, 1189-1197. [CrossRef] [PubMed]
301. Danielyan, L.; Schafer, R.; von Ameln-Mayerhofer, A.; Buadze, M.; Geisler, J.; Klopher, T.; Burkhardt, U.; Proksch, B.; Verleysdonk, S.; Ayturan, M.; et al. Intranasal delivery of cells to the brain. Eur. J. Cell Biol. 2009, 88, 315-324. [CrossRef] [PubMed]
302. Paul, C.; Samdani, A.F.; Betz, R.R.; Fischer, I.; Neuhuber, B. Grafting of human bone marrow stromal cells into spinal cord injury: A comparison of delivery methods. Spine 2009, 34, 328-334. [CrossRef] [PubMed]
303. Urdzikova, L.M.; Ruzicka, J.; LaBagnara, M.; Karova, K.; Kubinova, S.; Jirakova, K.; Murali, R.; Sykova, E.; Jhanwar-Uniyal, M.; Jendelova, P. Human mesenchymal stem cells modulate inflammatory cytokines after spinal cord injury in rat. Int. J. Mol. Sci. 2014, 15, 11275-11293. [CrossRef] [PubMed]
304. Yun, H.M.; Kim, H.S.; Park, K.R.; Shin, J.M.; Kang, A.R.; Lee, K.; Song, S.; Kim, Y.B.; Han, S.B.; Chung, H.M.; et al. Placenta-derived mesenchymal stem cells improve memory dysfunction in an Aß1-42-induced mouse model of Alzheimer’s disease. Cell Death Dis. 2013, 4, e958. [CrossRef] [PubMed]
305. Ikehara, S.; Li, M. Stem cell transplantation improves aging-related disease. Front. Cell Dev. Biol. 2014, 2, 16. [CrossRef] [PubMed]
306. Lee, J.K.; Jin, H.K.; Bae, J.S. Bone marrow-derived mesenchymal stem cells reduce brain amyloid-ß deposition and accelerate the activation of microglia in an acutely induced Alzheimer’s disease mouse model. Neurosci. Lett. 2009, 450, 136-141. [CrossRef] [PubMed]
307. Lee, J.K.; Jin, H.K.; Endo, S.; Schuchman, E.H.; Carter, J.E.; Bae, J.S. Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-ß deposition and rescues memory deficits in Alzheimer’s disease mice by modulation of immune responses. Stem Cells 2010, 28, 329-343. [CrossRef] [PubMed]
308. Butovsky, O.; Talpalar, A.E.; Ben-Yaakov, K.; Schwartz, M. Activation of microglia by aggregated ß-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-? and IL-4 render them protective. Mol. Cell. Neurosci. 2005, 29, 381-393. [CrossRef] [PubMed]
309. Butovsky, O.; Koronyo-Hamaoui, M.; Kunis, G.; Ophir, E.; Landa, G.; Cohen, H.; Schwartz, M. Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expression insulin-like growth factor 1. Proc. Natl. Acad. Sci. USA 2006, 103, 11784-11789. [CrossRef] [PubMed]
310. Nemeth, K.; Leelahavanichkul, A.; Yuen, P.S.; Mayer, B.; Parmelee, A.; Doi, K.; Robey, P.G.; Leelahavanichkul, K.; Koller, B.H.; Brown, J.M.; et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat. Med. 2009, 15, 42-49. [CrossRef] [PubMed]
311. Chen, W.W.; Blurton-Jones, M. Can stem cells be used to treat or model Alzheimer disease? Stem Cells 2012, 30, 2612-2618. [CrossRef] [PubMed]
312. Ma, S.; Xie, N.; Li, W.; Yuan, B.; Shi, Y.; Wang, Y. Immunobiology of mesenchymal stem cells. Cell Death Differ. 2014, 21, 216-225. [CrossRef] [PubMed]
313. Parr, A.M.; Kulbatski, I.; Tator, C.H. Transplantation of adult rat spinal cord stem/progenitor cells for spinal cord injury. J. Neurotrauma 2007, 24, 835-845. [CrossRef] [PubMed]
314. Munoz, J.R.; Stoutenger, B.R.; Robinson, A.P.; Spees, J.L.; Prockop, D.J. Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice. Proc. Natl. Acad. Sci. USA 2005, 102, 18171-18176. [CrossRef] [PubMed]
315. Kan, I.; Barhum, Y.; Melamed, E.; Offen, D. Mesenchymal stem cells stimulate endogenous neurogenesis in the subventricular zone of adult mice. Stem Cell Rev. 2011, 7, 404-412. [CrossRef] [PubMed]
316. Kim, S.; Chang, K.A.; Kim, J.A.; Park, H.G.; Ra, J.C.; Kim, H.S.; Suh, Y.H. The preventive and therapeutic effects of intravenous human adipose-derived stem cells in Alzheimer’s disease mice. PLoS ONE 2012, 7, e45757. [CrossRef] [PubMed]
317. Tfilin, M.; Sudai, E.; Merenlender, A.; Gispan, I.; Yadid, G.; Turgeman, G. Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior. Mol. Psychiatry 2010, 15, 1164-1175. [CrossRef] [PubMed]
318. Lu, S.; Lu, C.; Han, Q.; Li, J.; Du, Z.; Liao, L.; Zhao, R.C. Adipose-derived mesenchymal stem cells protect PC12 cells from glutamate excitotoxicity-induced apoptosis by upregulation of XIAP through PI3-K/Akt activation. Toxicology 2011, 279, 189-195. [CrossRef] [PubMed]
319. Lois, C.; Alvarez-Buylla, A. Long-distance neuronal migration in the adult mammalian brain. Science 1994, 264, 1145-1148. [CrossRef] [PubMed]
320. Alvarez-Buylla, A.; Garcia-Verdugo, J.M.; Tramontin, A.D. A unified hypothesis on the lineage of neuralstem cells. Nat. Rev. Neurosci. 2001, 2, 287-293. [CrossRef] [PubMed]
321. Cameron, H.A.; McKay, R.D. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J. Comp. Neurol. 2001, 435, 406-417. [CrossRef] [PubMed]
322. Zhao, C.; Deng, W.; Gage, F.H. Mechanisms and functional implications of adult neurogenesis. Cell 2008,132, 645-660. [CrossRef] [PubMed]
323. Ahlenius, H.; Visan, V.; Kokaia, M.; Lindvall, O.; Kokaia, Z. Neural stem and progenitor cells retain their potential for proliferation and differentiation into functional neurons despite lower number in aged brain.J. Neurosci. 2009, 29, 4408-4419. [CrossRef] [PubMed]
324. Miranda, C.J.; Braun, L.; Jiang, Y.; Hester, M.E.; Zhang, L.; Riolo, M.; Wang, H.; Rao, M.; Altura, R.A.;Kaspar, B.K. Aging brain microenvironment decreases hippocampal neurogenesis through Wnt-mediated survivin signaling. Aging Cell 2012, 11, 542-552. [CrossRef] [PubMed]
325. Lee, S.W.; Clemenson, G.D.; Gage, F.H. New neurons in an aged brain. Behav. Brain Res. 2012, 227, 497-507. [CrossRef] [PubMed]
326. Ferron, S.R.; Marques-Torrejon, M.A.; Mira, H.; Flores, I.; Taylor, K.; Blasco, M.A.; Farinas, I. Telomere shortening in neural stem cells disrupts neuronal differentiation and neuritogenesis. J. Neurosci. 2009, 29, 14394-14407. [CrossRef] [PubMed]
327. Blurton-Jones, M.; Kitazawa, M.; Martinez-Coria, H.; Castello, N.A.; Muller, F.J.; Loring, J.F.; Yamasaki, T.R.;Poon, W.W.; Green, K.N.; LaFerla, F.M. Neural stem cell improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc. Natl. Acad. Sci. USA 2009, 106, 13594-13599. [CrossRef] [PubMed]
328. Sugaya, K. Possible use of autologous stem cell therapies for Alzheimer’s disease. Curr. Alzheimer Res. 2005, 2, 367-376. [CrossRef] [PubMed]
329. Waldau, B.; Shetty, A.K. Behavior of neural stem cells in the Alzheimer brain. Cell. Mol. Life Sci. 2008, 65,2372-2384. [CrossRef] [PubMed]
330. Rivera, F.J.; Siebzehnrubl, F.A.; Kandasamy, M.; Couillard-Despres, S.; Caioni, M.; Poehler, A.M.;Berninger, B.; Sandner, B.; Bogdahn, U.; Goetz, M.; et al. Mesenchymal stem cells promote oligodendroglial differentiation in hippocampal slice cultures. Cell. Physiol. Biochem. 2009, 24, 317-324. [CrossRef] [PubMed]
331. Stewart, C.R.; Stuart, L.M.; Wilkinson, K.; van Gils, J.M.; Deng, J.; Halle, A.; Rayner, K.J.; Boyer, L.; Zhong, R.; Frazier, W.A.; et al. CD36 ligands promote sterile inflammation through assembly of a toll like receptor 4 and 6 heterodimer. Nat. Immunol. 2010, 11, 155-161. [CrossRef] [PubMed]
332. Reed-Geaghan, E.G.; Savage, J.C.; Hise, A.G.; Landreth, G.E. CD14 and Toll-like receptors 2 and 4 are required for fibrillar Aß-stimulated microglial activation. J. Neurosci. 2009, 29, 11982-11992. [CrossRef] [PubMed]
333. Lim, J.E.; Kou, J.; Song, M.; Pattanayak, A.; Jin, J.; Lalonde, R.; Fukuchi, K. MyD88 deficiency ameliorates ß-amyloidosis in an animal model of AD. Am. J. Pathol. 2011, 179, 1095-1103. [CrossRef] [PubMed]
334. Malm, T.; Koistinaho, J.; Kanninen, K. Utilization of APPswe/PS1dE9 transgenic mice in research of Alzheimer’s disease: Focus on gene therapy and cell-based therapy applications. Int. J. Alzheimers Dis. 2011, 2011. [CrossRef] [PubMed]
335. Fischer, W.; Wictorin, K.; Bjorklund, A.; Williams, L.P.; Varon, S.; Gage, F.H. Amelioration of cholinergicneuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature 1987, 329, 65-68. [CrossRef] [PubMed]
336. Pan, W.; Banks, W.A.; Kastin, A.J. Permeability of the blood-brain barrier to neurotrophins. Brain Res. 1998,788, 87-94. [CrossRef]
337. Williams, L.R. Hypophagia is induced by intracerebroventricular administration of nerve growth factor. Exp. Neurol. 1991, 113, 31-37. [CrossRef]
338. Tuszynski, M.H.; Thal, L.; Pay, M.; Salmon, D.P.; Sang U.H.; Bakay, R.; Patel, P.; Blesch, A.; Vahlsing, H.L.; Ho, G.; et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat. Med. 2005, 11, 551-555. [CrossRef] [PubMed]
339. Rafii, M.S.; Baumann, T.L.; Bakay, R.A.; Ostrove, J.M.; Siffert, J.; Fleisher, A.S.; Herzog, C.D.; Barba, D.;Pay, M.; Salmon, D.P.; et al. A phase 1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer’s disease. Alzheimers Dement. 2014, 10, 571-581.
340. Nagahara, A.H.; Merrill, D.A.; Coppola, G.; Tsukada, S.; Schroeder, B.E.; Shaked, G.M.; Wang, L.; Blesch, A.; Kim, A.; Conner, J.M.; et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat. Med. 2009, 15, 331-337. [CrossRef] [PubMed]
341. Connor, B.; Young, D.; Yan, Q.; Faull, R.L.; Synek, B.; Dragunow, M. Brain-derived neurotrophic factor is reduced in Alzheimer’s disease. Mol. Brain Res. 1997, 49, 71-81. [CrossRef]
342. Blurton-Jones, M.; Spencer, B.; Michael, S.; Castello, N.A.; Agazaryan, A.A.; Davis, J.L.; Muller, F.J.;Loring, J.F.; Masliah, E.; LaFerla, F.M. Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models. Stem Cell Res. Ther. 2014, 5, 46. [CrossRef] [PubMed]
343. Takahashi, K.; Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006, 126, 663-676. [CrossRef] [PubMed]
344. Lapasset, L.; Milhavet, O.; Prieur, A.; Besnard, E.; Babled, A.; Ait-Hamou, N.; Leschik, J.; Pellestor, F.; Ramirez, J.M.; de Vos, J.; et al. Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes Dev. 2011, 25, 2248-2253. [CrossRef] [PubMed]
345. Yagi, T.; Kosakai, A.; Ito, D.; Okada, Y.; Akamatsu, W.; Nihei, Y.; Nabetani, A.; Ishikawa, F.; Arai, Y.; Hirose, N.; et al. Establishment of induced pluripotent stem cells from centenarians for neurodegenerative disease research. PLoS ONE 2012, 7, e41572. [CrossRef] [PubMed]
346. Yagi, T.; Ito, D.; Okada, Y.; Akamatsu, W.; Nihei, Y.; Yoshizaki, T.; Yamanaka, S.; Okano, H.; Suzuki, N. Modeling familial Alzheimer’s disease with induced pluripotent stem cells. Hum. Mol. Genet. 2011, 20, 4530-4539. [CrossRef] [PubMed]
347. Israel, M.A.; Yuan, S.H.; Bardy, C.; Reyna, S.M.; Mu, Y.; Herrera, C.; Hefferan, M.P.; van Gorp, S.; Nazor, K.L.; Bascolo, F.S.; et al. Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 2012, 482, 216-220. [CrossRef] [PubMed]
348. Isobe, K.; Cheng, Z.; Nishio, N.; Suganya, T.; Tanaka, Y.; Ito, S. iPSCs, aging and age-related diseases. N. Biotechnol. 2014, 31, 411-421. [CrossRef] [PubMed]
349. Blasco, M.A. Telomere length, stem cells and aging. Nat. Chem. Biol. 2007, 3, 640-649.
350. Marion, R.M.; Strati, K.; Li, H.; Tejera, A.; Schoeftner, S.; Ortega, S.; Serrano, M.; Blasco, M.A. Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. Cell Stem Cell 2009, 4, 141-154. [CrossRef] [PubMed]
351. Huang, J.; Wang, F.; Okuka, M.; Liu, N.; Ji, G.; Ye, X.; Zuo, B.; Li, M.; Liang, P.; Ge, W.W.; et al. Association of telomere length with authentic pluripotency of ES/iPS cells. Cell Res. 2011, 21, 779-792. [CrossRef] [PubMed]
352. Golde, T.E.; Miller, V.M. Proteinopathy-induced neuronal senescence: A hypothesis for brain failure in Alzheimer’s and other neurodegenerative diseases. Alzheimers Res. Ther. 2009, 1, 5. [CrossRef] [PubMed]
353. Hunter, S.; Arendt, T.; Brayne, C. The senescence hypothesis of disease progression in Alzheimer’s disease: An integrated matrix of disease pathways for FAD and SAD. Mol. Neurobiol. 2013, 48, 556-570. [CrossRef] [PubMed]
354. Amemori, T.; Ermakova, I.V.; Buresova, O.; Zigova, T.; Racekova, E.; Bures, J. Brain transplants enhance rather than reduce the impairment of spatial memory and olfaction in bulbectomized rats. Behav. Neurosci. 1989, 103, 61-70. [CrossRef] [PubMed]
355. Vorhees, C.V.; Williams, M.T. Morris water maze: Procedures for assessing spatial and related forms of learning and memory. Nat. Protoc. 2006, 1, 848-858. [CrossRef] [PubMed]