Alzheimer's Disease and Hippocampal Adult Neurogenesis; Exploring Shared Mechanisms

Frontiers in Neuroscience

Volumn 10, Issue , 2016, Pages

  Hollands, Carolyn ^a   Bartolotti, Nancy ^a   Lazarov, Orly ^a  

^a UNIVERSITY OF ILLINOIS   (United States)

Author keywords

Alzheimer's disease; cognition; hippocampus; learning and memory; neurogenesis

Indexed keywords

EID: 85012241011     PISSN: 16624548     EISSN: 1662453X     Source Type: Journal    
DOI: 10.3389/fnins.2016.00178     Document Type: Review

References (107)

1. Ahlskog J. E., Geda Y. E., Graff-Radford N. R., Petersen R. C., (2011). Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin. Proc. 86, 876–884. 10.4065/mcp.2011.025221878600
2. Bartolotti N., Segura L., Lazarov O., (2015). Diminished CRE-induced plasticity is linked to memory deficits in familial Alzheimer's Disease mice. J. Alzheimers Dis. 50, 477–489. 10.3233/JAD-15065026682682
3. Baulac S., LaVoie M. J., Kimberly W. T., Strahle J., Wolfe M. S., Selkoe D. J., et al. (2003). Functional gamma-secretase complex assembly in Golgi/trans-Golgi network: interactions among presenilin, nicastrin, Aph1, Pen-2, and gamma-secretase substrates. Neurobiol. Dis. 14, 194–204. 10.1016/S0969-9961(03)00123-214572442
4. Bonds J. A., Kuttner-Hirshler Y., Bartolotti N., Tobin M. K., Pizzi M., Marr R., et al. (2015). Presenilin-1 dependent neurogenesis regulates hippocampal learning and memory. PLoS ONE 10:e0131266. 10.1371/journal.pone.013126626098332
5. Brickman A. M., Khan U. A., Provenzano F. A., Yeung L. K., Suzuki W., Schroeter H., et al. (2014). Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nat. Neurosci. 17, 1798–1803. 10.1038/nn.385025344629
6. Brickman A. M., Meier I. B., Korgaonkar M. S., Provenzano F. A., Grieve S. M., Siedlecki K. L., et al. (2012). Testing the white matter retrogenesis hypothesis of cognitive aging. Neurobiol. Aging 33, 1699–1715. 10.1016/j.neurobiolaging.2011.06.00121783280
7. Bullmann T., de Silva R., Holzer M., Mori H., Arendt T., (2007). Expression of embryonic tau protein isoforms persist during adult neurogenesis in the hippocampus. Hippocampus 17, 98–102. 10.1002/hipo.2025517183532
8. Caccamo A., Maldonado M. A., Bokov A. F., Majumder S., Oddo S., (2010). CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 107, 22687–22692. 10.1073/pnas.101285110821149712
9. Chenn A., Walsh C. A., (2003). Increased neuronal production, enlarged forebrains and cytoarchitectural distortions in beta-catenin overexpressing transgenic mice. Cereb. Cortex 13, 599–606. 10.1093/cercor/13.6.59912764034
10. Chevallier N. L., Soriano S., Kang D. E., Masliah E., Hu G., Koo E. H., (2005). Perturbed neurogenesis in the adult hippocampus associated with presenilin-1 A246E mutation. Am. J. Pathol. 167, 151–159. 10.1016/S0002-9440(10)62962-815972961
11. Choi S. H., Veeraraghavalu K., Lazarov O., Marler S., Ransohoff R. M., Ramirez J. M., et al. (2008). Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation. Neuron 59, 568–580. 10.1016/j.neuron.2008.07.03318760694
12. Chuang T. T., (2010). Neurogenesis in mouse models of Alzheimer's disease. Biochim. Biophys. Acta 1802, 872–880. 10.1016/j.bbadis.2009.12.00820056145
13. Chung Y. H., Kim E. J., Shin C. M., Joo K. M., Kim M. J., Woo H. W., et al. (2002). Age-related changes in CREB binding protein immunoreactivity in the cerebral cortex and hippocampus of rats. Brain Res. 956, 312–318. 10.1016/S0006-8993(02)03562-X12445700
14. Demars M., Hu Y. S., Gadadhar A., Lazarov O., (2010). Impaired neurogenesis is an early event in the etiology of familial Alzheimer's disease in transgenic mice. J. Neurosci. Res. 88, 2103–2117. 10.1002/jnr.2238720209626
15. Demars M. P., Bartholomew A., Strakova Z., Lazarov O., (2011). Soluble amyloid precursor protein: a novel proliferation factor of adult progenitor cells of ectodermal and mesodermal origin. Stem Cell Res. Ther. 2, 36. 10.1186/scrt7721878106
16. Demars M. P., Hollands C., Zhao K. D., Lazarov O., (2013). Soluble amyloid precursor protein-alpha rescues age-linked decline in neural progenitor cell proliferation. Neurobiol. Aging. 34, 2431–2440. 10.1016/j.neurobiolaging.2013.04.01623683827
17. De Strooper B., Annaert W., Cupers P., Saftig P., Craessaerts K., Mumm J. S., et al. (1999). A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518–522. 10.1038/1908310206645
18. De Strooper B., Saftig P., Craessaerts K., Vanderstichele H., Guhde G., Annaert W., et al. (1998). Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–390. 10.1038/349109450754
19. Dobrowolska J. A., Michener M. S., Wu G., Patterson B. W., Chott R., Ovod V., et al. (2014). CNS amyloid-beta, soluble APP-alpha and -beta kinetics during BACE inhibition. J. Neurosci. 34, 8336–8346. 10.1523/JNEUROSCI.0540-14.201424920637
20. Erickson K. I., Voss M. W., Prakash R. S., Basak C., Szabo A., Chaddock L., et al. (2011). Exercise training increases size of hippocampus and improves memory. Proc. Natl. Acad. Sci. U.S.A. 108, 3017–3022. 10.1073/pnas.101595010821282661
21. Eriksson P. S., Perfilieva E., Björk-Eriksson T., Alborn A. M., Nordborg C., Peterson D. A., et al. (1998). Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313–1317. 10.1038/33059809557
22. Ernst A., Alkass K., Bernard S., Salehpour M., Perl S., Tisdale J., et al. (2014). Neurogenesis in the striatum of the adult human brain. Cell 156, 1072–1083. 10.1016/j.cell.2014.01.04424561062
23. Flood J. F., Harris F. J., Morley J. E., (1996). Age-related changes in hippocampal drug facilitation of memory processing in SAMP8 mice. Neurobiol. Aging 17, 15–24. 10.1016/0197-4580(95)02007-18786798
24. Fuster-Matanzo A., de Barreda E. G., Dawson H. N., Vitek M. P., Avila J., Hernández F., (2009). Function of tau protein in adult newborn neurons. FEBS Lett. 583, 3063–3068. 10.1016/j.febslet.2009.08.01719695252
25. Fuster-Matanzo A., Llorens-Martín M., Jurado-Arjona J., Avila J., Hernández F., (2012). Tau protein and adult hippocampal neurogenesis. Front. Neurosci. 6:104. 10.3389/fnins.2012.0010422787440
26. Gadadhar A., Marr R., Lazarov O., (2011). Presenilin-1 regulates neural progenitor cell differentiation in the adult brain. J. Neurosci. 31, 2615–2623. 10.1523/JNEUROSCI.4767-10.201121325529
27. Ge S., Goh E. L., Sailor K. A., Kitabatake Y., Ming G. L., Song H., (2006). GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439, 589–593. 10.1038/nature0440416341203
28. Geinisman Y., Berry R. W., Disterhoft J. F., Power J. M., Van der Zee E. A., (2001). Associative learning elicits the formation of multiple-synapse boutons. J. Neurosci. 21, 5568–5573. 11466428
29. Geinisman Y., Ganeshina O., Yoshida R., Berry R. W., Disterhoft J. F., Gallagher M., (2004). Aging, spatial learning, and total synapse number in the rat CA1 stratum radiatum. Neurobiol. Aging 25, 407–416. 10.1016/j.neurobiolaging.2003.12.00115123345
30. Hamilton L. K., Aumont A., Julien C., Vadnais A., Calon F., Fernandes K. J., (2010). Widespread deficits in adult neurogenesis precede plaque and tangle formation in the 3xTg mouse model of Alzheimer's disease. Eur. J. Neurosci. 32, 905–920. 10.1111/j.1460-9568.2010.07379.x20726889
31. Hattiangady B., Shetty A. K., (2008). Aging does not alter the number or phenotype of putative stem/progenitor cells in the neurogenic region of the hippocampus. Neurobiol. Aging 29, 129–147. 10.1016/j.neurobiolaging.2006.09.01527035720
32. Herold S., Jagasia R., Merz K., Wassmer K., Lie D. C., (2011). CREB signalling regulates early survival, neuronal gene expression and morphological development in adult subventricular zone neurogenesis. Mol. Cell Neurosci. 46, 79–88. 10.1016/j.mcn.2010.08.00820801218
33. Hong X. P., Peng C. X., Wei W., Tian Q., Liu Y. H., Yao X. Q., et al. (2010). Essential role of tau phosphorylation in adult hippocampal neurogenesis. Hippocampus 20, 1339–1349. 10.1002/hipo.2071219816983
34. Hu Y. S., Long N., Pigino G., Brady S. T., Lazarov O., (2013). Molecular mechanisms of environmental enrichment: impairments in Akt/GSK3beta, neurotrophin-3 and CREB signaling. PLoS ONE 8:e64460. 10.1371/journal.pone.006446023700479
35. Hu Y. S., Xu P., Pigino G., Brady S. T., Larson J., Lazarov O., (2010). Complex environment experience rescues impaired neurogenesis, enhances synaptic plasticity, and attenuates neuropathology in familial Alzheimer's disease-linked APPswe/PS1{Delta}E9 mice. FASEB J. 24, 1667–1681. 10.1096/fj.09-13694520086049
36. Imayoshi I., Sakamoto M., Ohtsuka T., Takao K., Miyakawa T., Yamaguchi M., et al. (2008). Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat. Neurosci. 11, 1153–1161. 10.1038/nn.218518758458
37. Jagasia R., Steib K., Englberger E., Herold S., Faus-Kessler T., Saxe M., et al. (2009). GABA-cAMP response element-binding protein signaling regulates maturation and survival of newly generated neurons in the adult hippocampus. J. Neurosci. 29, 7966–7977. 10.1523/JNEUROSCI.1054-09.200919553437
38. Jin K., Peel A. L., Mao X. O., Xie L., Cottrell B. A., Henshall D. C., et al. (2004). Increased hippocampal neurogenesis in Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 101, 343–347. 10.1073/pnas.263479410014660786
39. Kandel E. R., (2012). The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol. Brain 5:14. 10.1186/1756-6606-5-1422583753
40. Kang D. E., Soriano S., Xia X., Eberhart C. G., De Strooper B., Zheng H., et al. (2002). Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis. Cell 110, 751–762. 10.1016/S0092-8674(02)00970-412297048
41. Kempermann G., Kuhn H. G., Gage F. H., (1997). More hippocampal neurons in adult mice living in an enriched environment. Nature 386, 493–495. 10.1038/386493a09087407
42. Kempermann G., Song H., Gage F. H., (2015). Neurogenesis in the Adult Hippocampus. Cold Spring Harb. Perspect. Med. 5:a018812. 10.1101/cshperspect.a01881226795749
43. Klusmann V., Evers A., Schwarzer R., Schlattmann P., Reischies F. M., Heuser I., et al. (2010). Complex mental and physical activity in older women and cognitive performance: a 6-month randomized controlled trial. J. Gerontol. A Biol. Sci. Med. Sci. 65, 680–688. 10.1093/gerona/glq05320418350
44. Komuro Y., Xu G., Bhaskar K., Lamb B. T., (2015). Human tau expression reduces adult neurogenesis in a mouse model of tauopathy. Neurobiol. Aging 36, 2034–2042. 10.1016/j.neurobiolaging.2015.03.00225863528
45. Kopan R., Ilagan M. X. G., (2009). The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137, 216–233. 10.1016/j.cell.2009.03.04519379690
46. Kudo K., Wati H., Qiao C., Arita J., Kanba S., (2005). Age-related disturbance of memory and CREB phosphorylation in CA1 area of hippocampus of rats. Brain Res. 1054, 30–37. 10.1016/j.brainres.2005.06.04516054117
47. Lange C., Mix E., Frahm J., Glass A., Müller J., Schmitt O., et al. (2011). Small molecule GSK-3 inhibitors increase neurogenesis of human neural progenitor cells. Neurosci. Lett. 488, 36–40. 10.1016/j.neulet.2010.10.07621056624
48. Lazarov O., Demars M. P., (2012). All in the family: how the APPs regulate neurogenesis. Front. Neurosci. 6:81. 10.3389/fnins.2012.0008122675290
49. Lazarov O., Hollands C., (2016). Hippocampal neurogenesis: learning to remember. Prog Neurobiol. 138-140:1-18. 10.1016/j.pneurobio.2015.12.00626855369
50. Lazarov O., Larson J., (2007). Research progress in Alzheimer's disease and dementia, in Environmental Enrichment: from Mouse AD Model to AD Therapy, Vol. 3. (New York, NY: Nova Science Publishers, Inc.), 303–328.
51. Lazarov O., Marr R. A., (2010). Neurogenesis and Alzheimer's disease: at the crossroads Exp. Neurol. 223, 267–281. 10.1016/j.expneurol.2009.08.00919699201
52. Lazarov O., Marr R. A., (2013). Of mice and men: neurogenesis, cognition and Alzheimer's disease. Front. Aging Neurosci. 5:43. 10.3389/fnagi.2013.0004323986699
53. Lazarov O., Mattson M. P., Peterson D. A., Pimplikar S. W., van Praag H., (2010). When neurogenesis encounters aging and disease. Trends Neurosci. 33, 569–579. 10.1016/j.tins.2010.09.00320961627
54. Lazarov O., Robinson J., Tang Y. P., Hairston I. S., Korade-Mirnics Z., Lee V. M., et al. (2005). Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell 120, 701–713. 10.1016/j.cell.2005.01.01515766532
55. Lie D. C., Colamarino S. A., Song H. J., Désiré L., Mira H., Consiglio A., et al. (2005). Wnt signalling regulates adult hippocampal neurogenesis. Nature 437, 1370–1375. 10.1038/nature0410816251967
56. Llorens-Martin M., Teixeira C. M., Fuster-Matanzo A., Jurado-Arjona J., Borrell V., Soriano E., et al. (2012). Tau isoform with three microtubule binding domains is a marker of new axons generated from the subgranular zone in the hippocampal dentate gyrus: implications for Alzheimer's disease. J. Alzheimers. Dis. 29, 921–930. 10.3233/JAD-2012-112057.22337826
57. Loewenbruck K. F., Fuchs B., Hermann A., Brandt M., Werner A., Kirsch M., et al. (2011). Proton MR spectroscopy of neural stem cells: does the proton-NMR peak at 1.28 ppm function as a biomarker for cell type or state? Rejuvenation Res. 14, 371–381. 10.1089/rej.2010.110227116703
58. Longo F. M., Yang T., Xie Y., Massa S. M., (2006). Small molecule approaches for promoting neurogenesis. Curr. Alzheimer Res. 3, 5–10. 10.2174/15672050677569708916472196
59. Lugert S., Basak O., Knuckles P., Haussler U., Fabel K., Götz M., et al. (2010). Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell Stem Cell 6, 445–456. 10.1016/j.stem.2010.03.01720452319
60. Ma Q. L., Harris-White M. E., Ubeda O. J., Simmons M., Beech W., Lim G. P., et al. (2007). Evidence of Abeta- and transgene-dependent defects in ERK-CREB signaling in Alzheimer's models. J. Neurochem. 103, 1594–1607. 10.1111/j.1471-4159.2007.04869.x17760871
61. MacMillan K. S., Naidoo J., Liang J., Melito L., Williams N. S., Morlock L., et al. (2011). Development of proneurogenic, neuroprotective small molecules. J. Am. Chem. Soc. 133, 1428–1437. 10.1021/ja108211m21210688
62. Manganas L. N., Zhang X., Li Y., Hazel R. D., Smith S. D., Wagshul M. E., et al. (2007). Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science 318, 980–985. 10.1126/science.114785117991865
63. Marathe S., Alberi L., (2015). Notch in memories: points to remember. Hippocampus 25, 1481–1488. 10.1002/hipo.2242625656274
64. Marathe S., Liu S., Brai E., Kaczarowski M., Alberi L., (2015). Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry. Cell Death Differ. 22, 1775–1784. 10.1038/cdd.2015.2325822340
65. Mayr B., Montminy M., (2001). Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat. Rev. Mol. Cell Biol. 2, 599–609. 10.1038/3508506811483993
66. McNeish J., Roach M., Hambor J., Mather R. J., Weibley L., Lazzaro J., et al. (2010). High-throughput screening in embryonic stem cell-derived neurons identifies potentiators of alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate-type glutamate receptors. J. Biol. Chem. 285, 17209–17217. 10.1074/jbc.M109.09881420212047
67. Merz K., Herold S., Lie D. C., (2011). CREB in adult neurogenesis–master and partner in the development of adult-born neurons? Eur. J. Neurosci. 33, 1078–1086. 10.1111/j.1460-9568.2011.07606.x21395851
68. Neely M. D., Litt M. J., Tidball A. M., Li G. G., Aboud A. A., Hopkins C. R., et al. (2012). DMH1, a highly selective small molecule BMP inhibitor promotes neurogenesis of hiPSCs: comparison of PAX6 and SOX1 expression during neural induction. ACS Chem. Neurosci. 3, 482–491. 10.1021/cn300029t22860217
69. Ninkovic J., Götz M., (2007). Signaling in adult neurogenesis: from stem cell niche to neuronal networks. Curr. Opin. Neurobiol. 17, 338–344. 10.1016/j.conb.2007.04.00617475475
70. Ortega-Martínez S., (2015). A new perspective on the role of the CREB family of transcription factors in memory consolidation via adult hippocampal neurogenesis. Front. Mol. Neurosci. 8:46. 10.3389/fnmol.2015.0004626379491
71. Ozgen N., Lau D. H., Shlapakova I. N., Sherman W., Feinmark S. J., Danilo P., Jr. et al. (2010). Determinants of CREB degradation and KChIP2 gene transcription in cardiac memory. Heart Rhythm 7, 964–970. 10.1016/j.hrthm.2010.03.02420346417
72. Petrik D., Jiang Y., Birnbaum S. G., Powell C. M., Kim M. S., Hsieh J., et al. (2012). Functional and mechanistic exploration of an adult neurogenesis-promoting small molecule. FASEB J. 26, 3148–3162. 10.1096/fj.11-20142622542682
73. Pieper A. A., Xie S., Capota E., Estill S. J., Zhong J., Long J. M., et al. (2010). Discovery of a proneurogenic, neuroprotective chemical. Cell 142, 39–51. 10.1016/j.cell.2010.06.01820603013
74. Pierfelice T., Alberi L., Gaiano N., (2011). Notch in the vertebrate nervous system: an old dog with new tricks. Neuron 69, 840–855. 10.1016/j.neuron.2011.02.03121382546
75. Porte Y., Buhot M. C., Mons N., (2008). Alteration of CREB phosphorylation and spatial memory deficits in aged 129T2/Sv mice. Neurobiol. Aging 29, 1533–1546. 10.1016/j.neurobiolaging.2007.03.02317478013
76. Rodríguez J. J., Jones V. C., Tabuchi M., Allan S. M., Knight E. M., LaFerla F. M., et al. (2008). Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer's disease. PLoS ONE 3:e2935. 10.1371/journal.pone.000293518698410
77. Ruscheweyh R., Willemer C., Krüger K., Duning T., Warnecke T., Sommer J., et al. (2011). Physical activity and memory functions: an interventional study. Neurobiol. Aging 32, 1304–1319. 10.1016/j.neurobiolaging.2009.08.00119716631
78. Sahay A., Scobie K. N., Hill A. S., O'Carroll C. M., Kheirbek M. A., Burghardt N. S., et al. (2011). Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472, 466–470. 10.1038/nature0981721460835
79. Sato N., Meijer L., Skaltsounis L., Greengard P., Brivanlou A. H., (2004). Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat. Med. 10, 55–63. 10.1038/nm97914702635
80. Schneider J. W., Gao Z., Li S., Farooqi M., Tang T. S., Bezprozvanny I., et al. (2008). Small-molecule activation of neuronal cell fate. Nat. Chem. Biol. 4, 408–410. 10.1038/nchembio.9518552832
81. Scott Bitner R., (2012). Cyclic AMP response element-binding protein (CREB) phosphorylation: a mechanistic marker in the development of memory enhancing Alzheimer's disease therapeutics. Biochem. Pharmacol. 83, 705–714. 10.1016/j.bcp.2011.11.00922119240
82. Selkoe D. J., Wolfe M. S., (2007). Presenilin: running with scissors in the membrane. Cell 131, 215–221. 10.1016/j.cell.2007.10.01217956719
83. Shi J., Longo F. M., Massa S. M., (2013). A small molecule p75(NTR) ligand protects neurogenesis after traumatic brain injury. Stem Cells 31, 2561–2574. 10.1002/stem.151623940017
84. Shimizu T., Kagawa T., Inoue T., Nonaka A., Takada S., Aburatani H., et al. (2008). Stabilized beta-catenin functions through TCF/LEF proteins and the Notch/RBP-Jkappa complex to promote proliferation and suppress differentiation of neural precursor cells. Mol. Cell Biol. 28, 7427–7441. 10.1128/MCB.01962-0718852283
85. Silva-Vargas V., Crouch E. E., Doetsch F., (2013). Adult neural stem cells and their niche: a dynamic duo during homeostasis, regeneration, and aging. Curr. Opin. Neurobiol. 23, 935–942. 10.1016/j.conb.2013.09.00424090877
86. Spalding K., Bergmann O., Alkass K., Bernard S., Salehpour M., Huttner H., et al. (2013). Dynamics of hippocampal neurogenesis in adult humans Cell. 153, 1219–1227 10.1016/j.cell.2013.05.00223746839
87. Stark S. M., Yassa M. A., Stark C. E., (2010). Individual differences in spatial pattern separation performance associated with healthy aging in humans. Learn. Mem. 17, 284–288. 10.1101/lm.176811020495062
88. Sun B., Halabisky B., Zhou Y., Palop J. J., Yu G., Mucke L., et al. (2009). Imbalance between GABAergic and glutamatergic transmission impairs adult neurogenesis in an animal model of Alzheimer's Disease. Cell Stem Cell 5, 624–633. 10.1016/j.stem.2009.10.00319951690
89. Tesco G., Kim T. W., Diehlmann A., Beyreuther K., Tanzi R. E., (1998). Abrogation of the presenilin 1/beta-catenin interaction and preservation of the heterodimeric presenilin 1 complex following caspase activation. J. Biol. Chem. 273, 33909–33914. 10.1074/jbc.273.51.339099852041
90. Tesco G., Tanzi R. E., (2000). GSK3 beta forms a tetrameric complex with endogenous PS1-CTF/NTF and beta-catenin. Effects of the D257/D385A and FAD-linked mutations. Ann. N.Y. Acad. Sci. 920, 227–232. 10.1111/j.1749-6632.2000.tb06927.x11193155
91. Toner C. K., Pirogovsky E., Kirwan C. B., Gilbert P. E., (2009). Visual object pattern separation deficits in nondemented older adults. Learn. Mem. 16, 338–342. 10.1101/lm.131510919403797
92. Tseng C. Y., Kao S. H., Wan C. L., Cho Y., Tung S. Y., Hsu H. J., (2014). Notch signaling mediates the age-associated decrease in adhesion of germline stem cells to the niche. PLoS Genet. 10:e1004888. 10.1371/journal.pgen.100488825521289
93. van Praag H., Christie B. R., Sejnowski T. J., Gage F. H., (1999a). Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc. Natl. Acad. Sci. U.S.A. 96, 13427–13431. 10.1073/pnas.96.23.1342710557337
94. van Praag H., Kempermann G., Gage F. H., (1999b). Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus [see comments]. Nat. Neurosci. 2, 266–270. 10.1038/636810195220
95. Villeda S. A., Luo J., Mosher K. I., Zou B., Britschgi M., Bieri G., et al. (2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94. 10.1038/nature1035721886162
96. Villeda S. A., Wyss-Coray T., (2013). The circulatory systemic environment as a modulator of neurogenesis and brain aging. Autoimmun. Rev. 12, 674–677. 10.1016/j.autrev.2012.10.01423201925
97. Vitolo O. V., Sant'Angelo A., Costanzo V., Battaglia F., Arancio O., Shelanski M., (2002). Amyloid beta -peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proc. Natl. Acad. Sci. U.S.A. 99, 13217–13221. 10.1073/pnas.17250419912244210
98. Wahlster L., Arimon M., Nasser-Ghodsi N., Post K. L., Serrano-Pozo A., Uemura K., et al. (2013). Presenilin-1 adopts pathogenic conformation in normal aging and in sporadic Alzheimer's disease. Acta Neuropathol. 125, 187–199. 10.1007/s00401-012-1065-623138650
99. Wang R., Dineley K. T., Sweatt J. D., Zheng H., (2004). Presenilin 1 familial Alzheimer's disease mutation leads to defective associative learning and impaired adult neurogenesis. Neuroscience 126, 305–312. 10.1016/j.neuroscience.2004.03.04815207348
100. Wang W., Pan Y. W., Zou J., Li T., Abel G. M., Palmiter R. D., et al. (2014). Genetic activation of ERK5 MAP kinase enhances adult neurogenesis and extends hippocampus-dependent long-term memory. J. Neurosci. 34, 2130–2147. 10.1523/JNEUROSCI.3324-13.201424501354
101. Warner-Schmidt J. L., Duman R. S., (2007). VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proc. Natl. Acad. Sci. U.S.A. 104, 4647–4652. 10.1073/pnas.061028210417360578
102. Wen P. H., Hof P. R., Chen X., Gluck K., Austin G., Younkin S. G., et al. (2004). The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice. Exp. Neurol. 188, 224–237. 10.1016/j.expneurol.2004.04.00215246822
103. Xia D., Watanabe H., Wu B., Lee S. H., Li Y., Tsvetkov E., et al. (2015). Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease. Neuron 85, 967–981. 10.1016/j.neuron.2015.02.01025741723
104. Xia X., Qian S., Soriano S., Wu Y., Fletcher A. M., Wang X. J., et al. (2001). Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis. Proc. Natl. Acad. Sci. U.S.A. 98, 10863–10868. 10.1073/pnas.19128419811517342
105. Yassa M. A., Mattfeld A. T., Stark S. M., Stark C. E., (2011). Age-related memory deficits linked to circuit-specific disruptions in the hippocampus. Proc. Natl. Acad. Sci. U.S.A. 108, 8873–8878. 10.1073/pnas.110156710821555581
106. Young-Pearse T. L., Bai J., Chang R., Zheng J. B., LoTurco J. J., Selkoe D. J., (2007). A critical function for beta-amyloid precursor protein in neuronal migration revealed by in utero RNA interference. J. Neurosci. 27, 14459–14469. 10.1523/JNEUROSCI.4701-07.200718160654
107. Young-Pearse T. L., Chen A. C., Chang R., Marquez C., Selkoe D. J., (2008). Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1. Neural Dev. 3:15. 10.1186/1749-8104-3-1518573216