Intracellular Aβ pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: A multidimensional study

Acta Neuropathologica Communications

Volumn 2, Issue 1, 2014, Pages

  Iulita, M Florencia ^a   Allard, Simon ^a   Richter, Luise ^a   Munter, Lisa Marie ^a   Ducatenzeiler, Adriana ^a   Weise, Christoph ^b   DoCarmo, Sonia ^a   Klein, William L ^c   Multhaup, Gerhard ^a   Cuello, A Claudio ^a  

^a MCGILL UNIVERSITY   (Canada)

^b FREIE UNIVERSITÄT BERLIN   (Germany)

^c NORTHWESTERN UNIVERSITY   (United States)

Author keywords

Alzheimer's disease; Amyloid ; APP; Intracellular A ; Pre clinical

Indexed keywords

AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN[1-40]; AMYLOID BETA-PROTEIN (1-42); AMYLOID PRECURSOR PROTEIN; PEPTIDE FRAGMENT; SECRETASE;

ADVERSE EFFECTS; ANIMAL; AUDITORY STIMULATION; BRAIN; CEREBROSPINAL FLUID; COGNITIVE DEFECT; CONDITIONING; DISEASE MODEL; FEAR; GENE EXPRESSION REGULATION; GENETICS; HUMAN; INTRACELLULAR FLUID; METABOLISM; MUTATION; PAIN MEASUREMENT; PATHOLOGY; PHYSIOLOGY; RAT; RECOGNITION; REGRESSION ANALYSIS; TRANSGENIC RAT;

ACOUSTIC STIMULATION; AMYLOID BETA-PEPTIDES; AMYLOID BETA-PROTEIN PRECURSOR; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; BRAIN; COGNITION DISORDERS; CONDITIONING (PSYCHOLOGY); DISEASE MODELS, ANIMAL; FEAR; GENE EXPRESSION REGULATION; HUMANS; INTRACELLULAR FLUID; MUTATION; PAIN MEASUREMENT; PEPTIDE FRAGMENTS; RATS; RATS, TRANSGENIC; RECOGNITION (PSYCHOLOGY); REGRESSION ANALYSIS;

EID: 84908191011     PISSN: None     EISSN: 20515960     Source Type: Journal    
DOI: 10.1186/2051-5960-2-61     Document Type: Article

References (72)

1. Prince M, Prina M, Guerchet M: World Alzheimer Report 2013. Journey of Caring. An analysis of long-term care for dementia. Alzheimer's Disease International, London; 2013:1-33.
2. Jack CR Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG, Pankratz VS, Donohue MC, Trojanowski JQ: Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 2013, 12: 207-216. 10.1016/S1474-4422(12)70291-0
3. Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, Szoeke C, Macaulay SL, Martins R, MaruffP, Ames D, Rowe CC, Masters CL, Australian Imaging B, Lifestyle Research G: Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol 2013, 12: 357-367. 10.1016/S1474-4422(13)70044-9
4. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC, Dominantly Inherited Alzheimer N: Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med 2012, 367: 795-804. 10.1056/NEJMoa1202753
5. Karran E, Mercken M, De Strooper B: The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 2011, 10: 698-712. 10.1038/nrd3505
6. Hardy JA, Higgins GA: Alzheimer's disease: the amyloid cascade hypothesis. Science 1992, 256: 184-185. 10.1126/science.1566067
7. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH: Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011, 7: 280-292. 10.1016/j.jalz.2011.03.003
8. Wirths O, Multhaup G, Czech C, Feldmann N, Blanchard V, Tremp G, Beyreuther K, Pradier L, Bayer TA: Intraneuronal APP/A beta trafficking and plaque formation in beta-amyloid precursor protein and presenilin-1 transgenic mice. Brain Pathol 2002, 12: 275-286.
9. Ferretti MT, Partridge V, Leon WC, Canneva F, Allard S, Arvanitis DN, Vercauteren F, Houle D, Ducatenzeiler A, Klein WL, Glabe CG, Szyf M, Cuello AC: Transgenic mice as a model of pre-clinical Alzheimer's disease. Curr Alzheimer Res 2011, 8: 4-23. 10.2174/156720511794604561
10. Leon WC, Canneva F, Partridge V, Allard S, Ferretti MT, DeWilde A, Vercauteren F, Atifeh R, Ducatenzeiler A, Klein W, Szyf M, Alhonen L, Cuello AC: A novel transgenic rat model with a full Alzheimer's-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment. J Alzheimers Dis 2010, 20: 113-126.
11. Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM: Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron 2005, 45: 675-688. 10.1016/j.neuron.2005.01.040
12. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM: Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 2003, 39: 409-421. 10.1016/S0896-6273(03)00434-3
13. Casas C, Sergeant N, Itier JM, Blanchard V, Wirths O, van der Kolk N, Vingtdeux V, van de Steeg E, Ret G, Canton T, Drobecq H, Clark A, Bonici B, Delacourte A, Benavides J, Schmitz C, Tremp G, Bayer TA, Benoit P, Pradier L: Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am J Pathol 2004, 165: 1289-1300. 10.1016/S0002-9440(10)63388-3
14. Gyure KA, Durham R, Stewart WF, Smialek JE, Troncoso JC: Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome. Arch Pathol Lab Med 2001, 125: 489-492.
15. Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ: Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis 1996, 3: 16-32. 10.1006/nbdi.1996.0003
16. Mori C, Spooner ET, Wisniewsk KE, Wisniewski TM, Yamaguch H, Saido TC, Tolan DR, Selkoe DJ, Lemere CA: Intraneuronal Abeta42 accumulation in Down syndrome brain. Amyloid 2002, 9: 88-102.
17. Gouras GK, Tsai J, Naslund J, Vincent B, Edgar M, Checler F, Greenfield JP, Haroutunian V, Buxbaum JD, Xu H, Greengard P, Relkin NR: Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 2000, 156: 15-20. 10.1016/S0002-9440(10)64700-1
18. Takahashi RH, Milner TA, Li F, Nam EE, Edgar MA, Yamaguchi H, Beal MF, Xu H, Greengard P, Gouras GK: Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol 2002, 161: 1869-1879. 10.1016/S0002-9440(10)64463-X
19. D'Andrea MR, Nagele RG, Wang HY, Peterson PA, Lee DH: Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer's disease. Histopathology 2001, 38: 120-134. 10.1046/j.1365-2559.2001.01082.x
20. Fernandez-Vizarra P, Fernandez AP, Castro-Blanco S, Serrano J, Bentura ML, Martinez-Murillo R, Martinez A, Rodrigo J: Intra- and extracellular Abeta and PHF in clinically evaluated cases of Alzheimer's disease. Histol Histopathol 2004, 19: 823-844.
21. Walsh DM, Tseng BP, Rydel RE, Podlisny MB, Selkoe DJ: The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. Biochemistry 2000, 39: 10831-10839. 10.1021/bi001048s
22. Takahashi RH, Almeida CG, Kearney PF, Yu F, Lin MT, Milner TA, Gouras GK: Oligomerization of Alzheimer's beta-amyloid within processes and synapses of cultured neurons and brain. J Neurosci 2004, 24: 3592-3599. 10.1523/JNEUROSCI.5167-03.2004
23. Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ: Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci U S A 2011, 108: 5819-5824. 10.1073/pnas.1017033108
24. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ: Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002, 416: 535-539. 10.1038/416535a
25. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ: Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 2008, 14: 837-842. 10.1038/nm1782
26. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL: Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A 1998, 95: 6448-6453. 10.1073/pnas.95.11.6448
27. Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH: Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci 2005, 8: 79-84. 10.1038/nn1372
28. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH: A specific amyloid-beta protein assembly in the brain impairs memory. Nature 2006, 440: 352-357. 10.1038/nature04533
29. Bruno MA, Leon WC, Fragoso G, Mushynski WE, Almazan G, Cuello AC: Amyloid beta-induced nerve growth factor dysmetabolism in Alzheimer disease. J Neuropathol Exp Neurol 2009, 68: 857-869. 10.1097/NEN.0b013e3181aed9e6
30. Winton MJ, Lee EB, Sun E, Wong MM, Leight S, Zhang B, Trojanowski JQ, Lee VM: Intraneuronal APP, not free Abeta peptides in 3xTg-AD mice: implications for tau versus Abeta-mediated Alzheimer neurodegeneration. J Neurosci 2011, 31: 7691-7699. 10.1523/JNEUROSCI.6637-10.2011
31. Cuello AC, Allard S, Ferretti MT: Evidence for the accumulation of Abeta immunoreactive material in the human brain and in transgenic animal models. Life Sci 2012, 91: 1141-1147. 10.1016/j.lfs.2012.05.020
32. Do Carmo S, Cuello AC: Modeling Alzheimer's disease in transgenic rats. Mol Neurodegener 2013, 8: 37. 10.1186/1750-1326-8-37
33. Pegg CC, He C, Stroink AR, Kattner KA, Wang CX: Technique for collection of cerebrospinal fluid from the cisterna magna in rat. J Neurosci Methods 2010, 187: 8-12. 10.1016/j.jneumeth.2009.12.002
34. Hu L, Wong TP, Cote SL, Bell KF, Cuello AC: The impact of Abeta-plaques on cortical cholinergic and non-cholinergic presynaptic boutons in alzheimer's disease-like transgenic mice. Neuroscience 2003, 121: 421-432. 10.1016/S0306-4522(03)00394-4
35. Côté SL, Cuello AC, Ribeiro-da-Silva A: Current protocols for light microscopy immunocytochemistry. In Immunohistochemistry II. Edited by: Cuello AC. West Sussex: Wiley; 1994:147-168.
36. Grant SM, Ducatenzeiler A, Szyf M, Cuello AC: Abeta immunoreactive material is present in several intracellular compartments in transfected, neuronally differentiated, P19 cells expressing the human amyloid beta-protein precursor. J Alzheimers Dis 2000, 2: 207-222.
37. Semenenko FM, Bramwell S, Sidebottom E, Cuello AC: Development of a mouse antiperoxidase secreting hybridoma for use in the production of a mouse PAP complex for immunocytochemistry and as a parent cell line in the development of hybrid hybridomas. Histochemistry 1985, 83: 405-408. 10.1007/BF00509200
38. Allard S, Leon WC, Pakavathkumar P, Bruno MA, Ribeiro-da-Silva A, Cuello AC: Impact of the NGF maturation and degradation pathway on the cortical cholinergic system phenotype. J Neurosci 2012, 32: 2002-2012. 10.1523/JNEUROSCI.1144-11.2012
39. Youmans KL, Tai LM, Kanekiyo T, Stine WB Jr, Michon SC, Nwabuisi-Heath E, Manelli AM, Fu Y, Riordan S, Eimer WA, Binder L, Bu G, Yu C, Hartley DM, LaDu MJ: Intraneuronal Abeta detection in 5xFAD mice by a new Abeta-specific antibody. Mol Neurodegener 2012, 7: 8. 10.1186/1750-1326-7-8
40. Lambert MP, Velasco PT, Chang L, Viola KL, Fernandez S, Lacor PN, Khuon D, Gong Y, Bigio EH, Shaw P, De Felice FG, Krafft GA, Klein WL: Monoclonal antibodies that target pathological assemblies of Abeta. J Neurochem 2007, 100: 23-35. 10.1111/j.1471-4159.2006.04157.x
41. Kaden D, Harmeier A, Weise C, Munter LM, AlthoffV, Rost BR, Hildebrand PW, Schmitz D, Schaefer M, Lurz R, Skodda S, Yamamoto R, Arlt S, Finckh U, Multhaup G: Novel APP/Abeta mutation K16N produces highly toxic heteromeric Abeta oligomers. EMBO Mol Med 2012, 4: 647-659. 10.1002/emmm.201200239
42. Ferretti MT, Allard S, Partridge V, Ducatenzeiler A, Cuello AC: Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology. J Neuroinflammation 2012, 9: 62. 10.1186/1742-2094-9-62
43. Bolte S, Cordelieres FP: A guided tour into subcellular colocalization analysis in light microscopy. J Microsc 2006, 224: 213-232. 10.1111/j.1365-2818.2006.01706.x
44. Gustafsson MG, Shao L, Carlton PM, Wang CJ, Golubovskaya IN, Cande WZ, Agard DA, Sedat JW: Three-dimensional resolution doubling in wide-field fluorescence microscopy by structured illumination. Biophys J 2008, 94: 4957-4970. 10.1529/biophysj.107.120345
45. Nader K, Schafe GE, Le Doux JE: Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 2000, 406: 722-726. 10.1038/35021052
46. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994, 53: 55-63. 10.1016/0165-0270(94)90144-9
47. Munter LM, Voigt P, Harmeier A, Kaden D, Gottschalk KE, Weise C, Pipkorn R, Schaefer M, Langosch D, Multhaup G: GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Abeta42. EMBO J 2007, 26: 1702-1712. 10.1038/sj.emboj.7601616
48. Munter LM, Botev A, Richter L, Hildebrand PW, AlthoffV, Weise C, Kaden D, Multhaup G: Aberrant amyloid precursor protein (APP) processing in hereditary forms of Alzheimer disease caused by APP familial Alzheimer disease mutations can be rescued by mutations in the APP GxxxG motif. J Biol Chem 2010, 285: 21636-21643. 10.1074/jbc. M109.088005
49. Mann DM, Jones D, Prinja D, Purkiss MS: The prevalence of amyloid (A4) protein deposits within the cerebral and cerebellar cortex in Down's syndrome and Alzheimer's disease. Acta Neuropathol 1990, 80: 318-327. 10.1007/BF00294651
50. Portelius E, Westman-Brinkmalm A, Zetterberg H, Blennow K: Determination of beta-amyloid peptide signatures in cerebrospinal fluid using immunoprecipitation-mass spectrometry. J Proteome Res 2006, 5: 1010-1016. 10.1021/pr050475v
51. De Strooper B, Simons M, Multhaup G, Van Leuven F, Beyreuther K, Dotti CG: Production of intracellular amyloid-containing fragments in hippocampal neurons expressing human amyloid precursor protein and protection against amyloidogenesis by subtle amino acid substitutions in the rodent sequence. EMBO J 1995, 14: 4932-4938.
52. Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002, 297: 353-356. 10.1126/science.1072994
53. Zlokovic BV, Yamada S, Holtzman D, Ghiso J, Frangione B: Clearance of amyloid beta-peptide from brain: transport or metabolism Nat Med 2000, 6: 718-719.
54. Glenner GG, Wong CW: Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984, 120: 885-890. 10.1016/S0006-291X(84)80190-4
55. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K: Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 1985, 82: 4245-4249. 10.1073/pnas.82.12.4245
56. Grant SM, Shankar SL, Chalmers-Redman RM, Tatton WG, Szyf M, Cuello AC: Mitochondrial abnormalities in neuroectodermal cells stably expressing human amyloid precursor protein (hAPP751). Neuroreport 1999, 10: 41-46. 10.1097/00001756-199901180-00008
57. Hartmann T, Bieger SC, Bruhl B, Tienari PJ, Ida N, Allsop D, Roberts GW, Masters CL, Dotti CG, Unsicker K, Beyreuther K: Distinct sites of intracellular production for Alzheimer's disease A beta40/42 amyloid peptides. Nat Med 1997, 3: 1016-1020. 10.1038/nm0997-1016
58. Wertkin AM, Turner RS, Pleasure SJ, Golde TE, Younkin SG, Trojanowski JQ, Lee VM: Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular beta-amyloid or A4 peptides. Proc Natl Acad Sci U S A 1993, 90: 9513-9517. 10.1073/pnas.90.20.9513
59. Turner RS, Suzuki N, Chyung AS, Younkin SG, Lee VM: Amyloids beta40 and beta42 are generated intracellularly in cultured human neurons and their secretion increases with maturation. J Biol Chem 1996, 271: 8966-8970. 10.1074/jbc.271.15.8966
60. Mochizuki A, Tamaoka A, Shimohata A, Komatsuzaki Y, Shoji S: Abeta42-positive non-pyramidal neurons around amyloid plaques in Alzheimer's disease. Lancet 2000, 355: 42-43. 10.1016/S0140-6736(99)04937-5
61. Philipson O, Lannfelt L, Nilsson LN: Genetic and pharmacological evidence of intraneuronal Abeta accumulation in APP transgenic mice. FEBS Lett 2009, 583: 3021-3026. 10.1016/j.febslet.2009.08.009
62. Echeverria V, Ducatenzeiler A, Dowd E, Janne J, Grant SM, Szyf M, Wandosell F, Avila J, Grimm H, Dunnett SB, Hartmann T, Alhonen L, Cuello AC: Altered mitogen-activated protein kinase signaling, tau hyperphosphorylation and mild spatial learning dysfunction in transgenic rats expressing the beta-amyloid peptide intracellularly in hippocampal and cortical neurons. Neuroscience 2004, 129: 583-592. 10.1016/j.neuroscience.2004.07.036
63. Hashimoto M, Bogdanovic N, Volkmann I, Aoki M, Winblad B, Tjernberg LO: Analysis of microdissected human neurons by a sensitive ELISA reveals a correlation between elevated intracellular concentrations of Abeta42 and Alzheimer's disease neuropathology. Acta Neuropathol 2010, 119: 543-554. 10.1007/s00401-010-0661-6
64. Iwatsubo T, Mann DM, Odaka A, Suzuki N, Ihara Y: Amyloid beta protein (A beta) deposition: A beta 42(43) precedes A beta 40 in Down syndrome. Ann Neurol 1995, 37: 294-299. 10.1002/ana.410370305
65. Ferretti MT, Bruno MA, Ducatenzeiler A, Klein WL, Cuello AC: Intracellular Abeta-oligomers and early inflammation in a model of Alzheimer's disease. Neurobiol Aging 2012, 33: 1329-1342. 10.1016/j.neurobiolaging.2011.01.007
66. Heun R, Mazanek M, Atzor KR, Tintera J, Gawehn J, Burkart M, Gansicke M, Falkai P, Stoeter P: Amygdala-hippocampal atrophy and memory performance in dementia of Alzheimer type. Dement Geriatr Cogn Disord 1997, 8: 329-336. 10.1159/000106651
67. Mizuno K, Wakai M, Takeda A, Sobue G: Medial temporal atrophy and memory impairment in early stage of Alzheimer's disease: an MRI volumetric and memory assessment study. J Neurol Sci 2000, 173: 18-24. 10.1016/S0022-510X(99)00289-0
68. Yankner BA, Dawes LR, Fisher S, Villa-KomaroffL, Oster-Granite ML, Neve RL: Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. Science 1989, 245: 417-420. 10.1126/science.2474201
69. Mitani Y, Yarimizu J, Saita K, Uchino H, Akashiba H, Shitaka Y, Ni K, Matsuoka N: Differential effects between gamma-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice. J Neurosci: J Soc Neurosci 2012, 32: 2037-2050. 10.1523/JNEUROSCI.4264-11.2012
70. Jinno S, Araki K, Matsumoto Y, Suh YH, Yamamoto T: Selective apoptosis induction in the hippocampal mossy fiber pathway by exposure to CT105, the C-terminal fragment of Alzheimer's amyloid precursor protein. Brain Res 2009, 1249: 68-78.
71. Nalbantoglu J, Tirado-Santiago G, Lahsaini A, Poirier J, Goncalves O, Verge G, Momoli F, Welner SA, Massicotte G, Julien JP, Shapiro ML: Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature 1997, 387: 500-505. 10.1038/387500a0
72. Scarmeas N, Stern Y: Cognitive reserve and lifestyle. J Clin Exp Neuropsychol 2003, 25: 625-633. 10.1076/jcen.25.5.625.14576