Alzheimer's Disease Risk Factor Pyk2 Mediates Amyloid-β-Induced Synaptic Dysfunction and Loss
Open accessAbstract
Dozens of genes have been implicated in late onset Alzheimer's disease (AD) risk, but none has a defined mechanism of action in neurons. Here, we show that the risk factor Pyk2 (PTK2B) localizes specifically to neurons in adult brain. Absence of Pyk2 has no major effect on synapse formation or the basal parameters of synaptic transmission in the hippocampal Schaffer collateral pathway. However, the induction of synaptic LTD is suppressed in Pyk2-null slices. In contrast, deletion of Pyk2 expression does not alter LTP under control conditions. Of relevance for AD pathophysiology, Pyk2−/−slices are protected from amyloid-β-oligomer (Aβo)-induced suppression of LTP in hippocampal slices. Acutely, a Pyk2 kinase inhibitor also prevents Aβo-induced suppression of LTP in WT slices. Female and male transgenic AD model mice expressing APPswe/PSEN1ΔE9 require Pyk2 for age-dependent loss of synaptic markers and for impairment of learning and memory. However, absence of Pyk2 does not alter Aβ accumulation or gliosis. Therefore, the Pyk2 risk gene is directly implicated in a neuronal Aβo signaling pathway impairing synaptic anatomy and function. SIGNIFICANCE STATEMENT Genetic variation at the Pyk2 (PTK2B) locus is a risk for late onset Alzheimer's disease (AD), but the pathophysiological role of Pyk2 is not clear. Here, we studied Pyk2 neuronal function in mice lacking expression with and without transgenes generating amyloid-β (Aβ) plaque pathology. Pyk2 is not required for basal synaptic transmission or LTP, but participates in LTD. Hippocampal slices lacking Pyk2 are protected from AD-related Aβ oligomer suppression of synaptic plasticity. In transgenic AD model mice, deletion of Pyk2 rescues synaptic loss and learning/memory deficits. Therefore, Pyk2 plays a central role in AD-related synaptic dysfunction mediating Aβ-triggered dysfunction.
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Pyk2 is involved in long-term depression (LTD).
“Consistently, Pyk2 was involved in long-term potentiation (LTP) through the regulation of Src in an activity-dependent fashion [57], and in long-term depression (LTD) [55, 109].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [109]
Pyk2 mediates Aβ-dependent synapse loss.
“Finally, Pyk2 has recently been shown to mediate Aβ-dependent synapse loss [109].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [109]
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Neuroinflammation in Alzheimer's disease
Heneka, M. T., Carson, M. J., Khoury, J. E., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., et al. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)70016-5 · Cited by 6,226 · see citing works
Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
(EADI), E. A. D. I., Lambert, J.-C., (GERAD), G. A. E. R. I. A. D., Alzheimer's Disease Genetic Consortium (ADGC), (CHARGE), C. F. H. A. A. R. I. G. E., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2802 · Cited by 4,336 · see citing works
Complement and microglia mediate early synapse loss in Alzheimer mouse models
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., et al. (2016) · Science · doi:10.1126/science.aad8373 · Cited by 3,343 · cited 16× · see citing works
“The present study demonstrates that the AD risk gene product Pyk2 is expressed in neurons and contributes to synaptic LTD, but is not required for basal synaptic function or LTP.”
BackgroundInfluentialThe Cellular Phase of Alzheimer’s Disease
De Strooper, B., & Karran, E. (2016) · Cell · doi:10.1016/j.cell.2015.12.056 · Cited by 1,990 · see citing works
Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers
Laurén, J., Gimbel, D. A., Nygaard, H. B., Gilbert, J. W., & Strittmatter, S. M. (2009) · Nature · doi:10.1038/nature07761 · Cited by 1,560 · see citing works
Self-citationUm, J. W., Kaufman, A. C., Kostylev, M., Heiss, J. K., Stagi, M., Takahashi, H., Kerrisk, M. E., Vortmeyer, A., Wisniewski, T., Koleske, A. J., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.036 · Cited by 572 · see citing works
Self-citation<scp>F</scp>yn inhibition rescues established memory and synapse loss in <scp>A</scp>lzheimer mice
Kaufman, A. C., Salazar, S. V., Haas, L. T., Yang, J., Kostylev, M. A., Jeng, A. T., Robinson, S. A., Gunther, E. C., van Dyck, C. H., Nygaard, H. B., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24394 · Cited by 314 · see citing works
Self-citationDourlen, P., Fernandez-Gomez, F. J., Dupont, C., Grenier-Boley, B., Bellenguez, C., Obriot, H., Caillierez, R., Sottejeau, Y., Chapuis, J., Bretteville, A., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.59 · Cited by 118 · see citing works
PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer's disease
Giralt, A., de Pins, B., Cifuentes-Díaz, C., López-Molina, L., Farah, A. T., Tible, M., Deramecourt, V., Arold, S. T., Ginés, S., Hugon, J., et al. (2018) · Experimental Neurology · doi:10.1016/j.expneurol.2018.05.020 · Cited by 64 · see citing works
Flagged first, then by citations
Research works printed but not linked: 59
- Alzheimer's Association (2012) 2012 Alzheimer's disease facts and figures. Alzheimers Dement 8:131-168. CrossRef Medline · DOI
- Andreev J, Galisteo ML, Kranenburg O, Logan SK, Chiu ES, Okigaki M, Cary LA, Moolenaar WH, Schlessinger J (2001) Src and Pyk2 mediate G-protein-coupled receptor activation of epidermal growth factor recep- tor (EGFR) but are not required for coupling to the mitogen-activated protein (MAP) kinase signaling cascade. J Biol Chem 276:20130 -20135. CrossRef Medline · DOI
- Bartos JA, Ulrich JD, Li H, Beazely MA, Chen Y, Macdonald JF, Hell JW (2010) Postsynaptic clustering and activation of Pyk2 by PSD-95. J Neu- rosci 30:449 -463. CrossRef Medline · DOI
- Chan G, White CC, Winn PA, Cimpean M, Replogle JM, Glick LR, Cuerdon NE, Ryan KJ, Johnson KA, Schneider JA, Bennett DA, Chibnik LB, Sper- ling RA, Bradshaw EM, De Jager PL (2015) CD33 modulates TREM2: convergence of Alzheimer loci. Nat Neurosci 18:1556 -1558. CrossRef Medline · DOI · Paper page
- Collins M, Bartelt RR, Houtman JC (2010a) T cell receptor activation leads to two distinct phases of Pyk2 activation and actin cytoskeletal rearrange- ment in human T cells. Mol Immunol 47:1665-1674. CrossRef Medline · DOI
- Collins M, Tremblay M, Chapman N, Curtiss M, Rothman PB, Houtman JC (2010b) The T cell receptor-mediated phosphorylation of Pyk2 tyrosines 402 and 580 occurs via a distinct mechanism than other receptor systems. J Leukoc Biol 87:691-701. CrossRef Medline · DOI
- Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apo- lipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261:921-923. CrossRef Medline · DOI · Paper page
- Dikic I, Tokiwa G, Lev S, Courtneidge SA, Schlessinger J (1996) A role for Pyk2 and src in linking G-protein-coupled receptors with MAP kinase activation. Nature 383:547-550. CrossRef Medline · DOI
- Filali M, Lalonde R (2009) Age-related cognitive decline and nesting behav- ior in an APPswe/PS1 bigenic model of Alzheimer's disease. Brain Res 1292:93-99. CrossRef Medline · DOI · Paper page
- Gimbel DA, Nygaard HB, Coffey EE, Gunther EC, Laure ´n J, Gimbel ZA, Strittmatter SM (2010) Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J Neurosci 30:6367-6374. CrossRef Medline · DOI · Paper page
- Giralt A, Coura R, Girault JA (2016) Pyk2 is essential for astrocytes mobility following brain lesion. Glia 64:620 -634. CrossRef Medline · DOI
- Giralt A, Brito V, Chevy Q, Simonnet C, Otsu Y, Cifuentes-Díaz C, de Pins B, Coura R, Alberch J, Gine ´s S, Poncer JC, Girault JA (2017) Pyk2 modu- lates hippocampal excitatory synapses and contributes to cognitive defi- cits in a Huntington's disease model. Nat Commun 8:15592. CrossRef Medline · DOI · Paper page
- Guerreiro R, et al. (2013) TREM2 variants in Alzheimer's disease. N Engl J Med 368:117-127. CrossRef Medline · DOI · Paper page
- Haas LT, Strittmatter SM (2016) Oligomers of amyloid beta prevent physi- ological activation of the cellular prion protein-metabotropic glutamate receptor 5 complex by glutamate in Alzheimer disease. J Biol Chem 291: 17112-17121. CrossRef Medline · DOI · Paper page
- Haas LT, Salazar SV, Kostylev MA, Um JW, Kaufman AC, Strittmatter SM (2016) Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer's disease. Brain 139:526 -546. CrossRef Medline · DOI
- Haas LT, Salazar SV, Smith LM, Zhao HR, Cox TO, Herber CS, Degnan AP, Balakrishnan A, Macor JE, Albright CF, Strittmatter SM (2017) Silent allosteric modulation of mGluR5 maintains glutamate signaling while rescuing Alzheimer's mouse phenotypes. Cell Rep 20:76 -88. CrossRef Medline · DOI
- Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297:353-356. CrossRef Medline · DOI · Paper page
- Hartigan JA, Xiong WC, Johnson GV (2001) Glycogen synthase kinase 3beta is tyrosine phosphorylated by PYK2. Biochem Biophys Res Com- mun 284:485-489. CrossRef Medline · DOI · Paper page
- Heiss JK, Barrett J, Yu Z, Haas LT, Kostylev MA, Strittmatter SM (2017) Early activation of experience-independent dendritic spine turnover in a mouse model of Alzheimer's disease. Cereb Cortex 27:3660 -3674. CrossRef Medline · DOI
- Holtzman DM, Morris JC, Goate AM (2011) Alzheimer's disease: the chal- lenge of the second century. Sci Transl Med 3:77sr71. CrossRef Medline · DOI · Paper page
- Hsin H, Kim MJ, Wang CF, Sheng M (2010) Proline-rich tyrosine kinase 2 regulates hippocampal long-term depression. J Neurosci 30:11983- 11993. CrossRef Medline · DOI · Paper page
- Huang Y, Lu W, Ali DW, Pelkey KA, Pitcher GM, Lu YM, Aoto H, Roder JC, Sasaki T, Salter MW, MacDonald JF (2001) CAKbeta/Pyk2 kinase is a signaling link for induction of long-term potentiation in CA1 hippocam- pus. Neuron 29:485-496. CrossRef Medline · DOI · Paper page
- Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wo ¨lfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Go ¨tz J (2010) Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell 142:387-397. CrossRef Medline · DOI · Paper page
- Jankowsky JL, Xu G, Fromholt D, Gonzales V, Borchelt DR (2003) Environ- mental enrichment exacerbates amyloid plaque formation in a transgenic mouse model of Alzheimer disease. J Neuropathol Exp Neurol 62:1220 - 1227. CrossRef Medline · DOI
- Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Cope- land NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR (2004) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13:159 -170. CrossRef Medline · DOI · Paper page
- Jonsson T, et al. (2013) Variant of TREM2 associated with the risk of Alz- heimer's disease. N Engl J Med 368:107-116. CrossRef Medline · DOI · Paper page
- Karch CM, Goate AM (2015) Alzheimer's disease risk genes and mecha- nisms of disease pathogenesis. Biol Psychiatry 77:43-51. CrossRef Medline · DOI · Paper page
- Kaufman SK, Sanders DW, Thomas TL, Ruchinskas AJ, Vaquer-Alicea J, Sharma AM, Miller TM, Diamond MI (2016) tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo. Neuron 92:796 -812. CrossRef Medline · DOI · Paper page
- Kinoshita Y, Hunter RG, Gray JD, Mesias R, McEwen BS, Benson DL, Kohtz DS (2014) Role for NUP62 depletion and PYK2 redistribution in den- dritic retraction resulting from chronic stress. Proc Natl Acad Sci U S A 111:16130 -16135. CrossRef Medline · DOI
- 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 (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A 95:6448 -6453. CrossRef Medline · DOI · Paper page
- Li C, Go ¨tz J (2018) Pyk2 is a novel tau tyrosine kinase that is regulated by the tyrosine kinase fyn. J Alzheimers Dis 64:205-221. CrossRef Medline · DOI · Paper page
- Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D (2009) Soluble oligomers of amyloid beta protein facilitate hippocampal long- term depression by disrupting neuronal glutamate uptake. Neuron 62: 788 -801. CrossRef Medline · DOI · Paper page
- Menegon A, Burgaya F, Baudot P, Dunlap DD, Girault JA, Valtorta F (1999) FAKϩ and PYK2/CAKbeta, two related tyrosine kinases highly expressed in the central nervous system: similarities and differences in the expres- sion pattern. Eur J Neurosci 11:3777-3788. CrossRef Medline · DOI
- Mitra SK, Hanson DA, Schlaepfer DD (2005) Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol 6:56 -68. CrossRef Medline · DOI
- Nixon RA (2013) The role of autophagy in neurodegenerative disease. Nat Med 19:983-997. CrossRef Medline · DOI · Paper page
- Okigaki M, Davis C, Falasca M, Harroch S, Felsenfeld DP, Sheetz MP, Sch- lessinger J (2003) Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration. Proc Natl Acad Sci U S A 100: 10740 -10745. CrossRef Medline · DOI
- Park HJ, Westin CF, Kubicki M, Maier SE, Niznikiewicz M, Baer A, Frumin M, Kikinis R, Jolesz FA, McCarley RW, Shenton ME (2004) White mat- ter hemisphere asymmetries in healthy subjects and in schizophrenia: a diffusion tensor MRI study. Neuroimage 23:213-223. CrossRef Medline · DOI · Paper page
- Park JH, Widi GA, Gimbel DA, Harel NY, Lee DH, Strittmatter SM (2006) Subcutaneous nogo receptor removes brain amyloid-beta and improves spatial memory in Alzheimer's transgenic mice. J Neurosci 26:13279 - 13286. CrossRef Medline · DOI
- Pimenova AA, Raj T, Goate AM (2018) Untangling genetic risk for Alzhei- mer's disease. Biol Psychiatry 83:300 -310. CrossRef Medline · DOI · Paper page
- Purro SA, Nicoll AJ, Collinge J (2018) Prion protein as a toxic acceptor of amyloid-beta oligomers. Biol Psychiatry 83:358 -368. CrossRef Medline · DOI
- Qian D, Lev S, van Oers NS, Dikic I, Schlessinger J, Weiss A (1997) Tyrosine phosphorylation of Pyk2 is selectively regulated by fyn during TCR sig- naling. J Exp Med 185:1253-1259. CrossRef Medline · DOI
- Salazar SV, Strittmatter SM (2017) Cellular prion protein as a receptor for amyloid-beta oligomers in Alzheimer's disease. Biochem Biophys Res Commun 483:1143-1147. CrossRef Medline · DOI
- Salazar SV, Gallardo C, Kaufman AC, Herber CS, Haas LT, Robinson S, Manson JC, Lee MK, Strittmatter SM (2017) Conditional deletion of Prnp rescues behavioral and synaptic deficits after disease onset in trans- genic Alzheimer's disease. J Neurosci 37:9207-9221. CrossRef Medline · DOI
- Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A, Barker SJ, Foley AC, Thorpe JR, Serpell LC, Miller TM, Grinberg LT, Seeley WW, Diamond MI (2014) Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82:1271-1288. CrossRef Medline · DOI · Paper page
- Sayas CL, Ariaens A, Ponsioen B, Moolenaar WH (2006) GSK-3 is activated by the tyrosine kinase Pyk2 during LPA1-mediated neurite retraction. Mol Biol Cell 17:1834 -1844. CrossRef Medline · DOI · Paper page
- Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006) Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment. Neuro- biol Aging 27:1372-1384. CrossRef Medline · DOI · Paper page
- Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ (2007) Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impair- ment. Neurology 68:1501-1508. CrossRef Medline · DOI · Paper page
- Schnell SA, Staines WA, Wessendorf MW (1999) Reduction of lipofuscin- like autofluorescence in fluorescently labeled tissue. J Histochem Cy- tochem 47:719 -730. CrossRef Medline · DOI
- Selkoe DJ (2002) Alzheimer's disease is a synaptic failure. Science 298:789 - 791. CrossRef Medline · DOI · Paper page
- Selkoe DJ (2011) Alzheimer's disease. Cold Spring Harb Perspect Biol 3:a004457. CrossRef Medline · DOI
- 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 (2008) Amyloid-beta protein dimers isolated di- rectly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 14:837-842. CrossRef Medline · DOI · Paper page
- Tse KW, Lin KB, Dang-Lawson M, Guzman-Perez A, Aspnes GE, Buckbinder L, Gold MR (2012) Small molecule inhibitors of the Pyk2 and FAK ki- nases modulate chemoattractant-induced migration, adhesion and akt activation in follicular and marginal zone B cells. Cell Immunol 275:47- 54. CrossRef Medline · DOI
- Um JW, Nygaard HB, Heiss JK, Kostylev MA, Stagi M, Vortmeyer A, Wis- niewski T, Gunther EC, Strittmatter SM (2012) Alzheimer amyloid-beta oligomer bound to postsynaptic prion protein activates fyn to impair neurons. Nat Neurosci 15:1227-1235. CrossRef Medline · DOI
- Usardi A, Pooler AM, Seereeram A, Reynolds CH, Derkinderen P, Anderton B, Hanger DP, Noble W, Williamson R (2011) Tyrosine phosphoryla- tion of tau regulates its interactions with fyn SH2 domains, but not SH3 domains, altering the cellular localization of tau. FEBS J 278:2927-2937. CrossRef Medline · DOI
- Villasana LE, Klann E, Tejeda-Simon MV (2006) Rapid isolation of synap- toneurosomes and postsynaptic densities from adult mouse hippocam- pus. J Neurosci Meth 158:30 -36. CrossRef Medline · DOI
- Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta pro- tein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535-539. CrossRef Medline · DOI · Paper page
- Zhang R, Xue G, Wang S, Zhang L, Shi C, Xie X (2012) Novel object recog- nition as a facile behavior test for evaluating drug effects in AbetaPP/PS1 Alzheimer's disease mouse model. J Alzheimers Dis 31:801-812. CrossRef Medline · DOI
- Zhao M, Finlay D, Zharkikh I, Vuori K (2016) Novel role of Src in priming Pyk2 phosphorylation. PLoS One 11:e0149231. CrossRef Medline · DOI
- Zhao N, Liu CC, Qiao W, Bu G (2018) Apolipoprotein E, receptors, and modulation of Alzheimer's disease. Biol Psychiatry 83:347-357. CrossRef Medline · DOI · Paper page
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- Authors
- Salazar, S. V., Cox, T. O., Lee, S., Brody, A. H., Chyung, A. S., Haas, L. T., & Strittmatter, S. M.
- Affiliations
- Yale University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2018-12-05
- Volume
- 39
- Issue
- 4
- Pages
- 758-772
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6343652
- OpenAlex
- W2902154838
- Cited by
- 77
- References
- 9
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 5 · 2023: 8 · 2022: 14 · 2021: 19 · 2020: 9 · 2019: 8
- FWCI
- 5.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (RF1AG053000, P50AG047270, R01AG034924)
- National Institute of Neurological Disorders and Stroke (R35NS097283, T32NS007224)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Pyk2, Alzheimer's disease, amyloid-beta oligomers, synaptic dysfunction, synaptic loss, long-term depression, long-term potentiation, hippocampus, Schaffer collaterals, learning and memory impairment, neuronal signaling
- MeSH terms
- Alzheimer Disease, Animals, Behavior, Animal, Female, Gliosis, Learning, Male, Memory, Mice, Inbred C57BL, Mice, Transgenic, Risk Factors, Synapses, Signal Transduction, Amyloid beta-Peptides, Long-Term Potentiation, Mice, Knockout, Long-Term Synaptic Depression, Mice, Focal Adhesion Kinase 2
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