Synaptic Dysfunction in Alzheimer’s Disease: A Narrative Review of Neuronal Changes

Abstract

Alzheimer's disease (AD) is a prevalent neurological condition among the elderly, characterized by progressive cognitive decline and is the most common form of dementia. Neurofibrillary tangles (NFTs) and amyloid beta (Aβ) plaques are the hallmark pathological features of AD. However, substantial experimental evidence suggests that alterations in synaptic function, leading to cognitive impairment in AD patients, may represent early indicators of the disease. In this review, we classify, discuss, and describe the primary findings related to changes in the neurophysiological mechanisms of pre- and post-synaptic structure and function underlying AD. Both mechanical and chemical impairments caused by Aβ plaques and NFTs disrupt synaptic function, leading to compromised long-term potentiation (LTP) and long-term depression (LTD), as well as alterations in pre- and post-synaptic proteins.

Keywords

• Alzheimer's disease
• Pre-synaptic structures
• Post-synaptic structures
• Synaptic dysfunction

Thanks

Figure 2 was created with BioRender.com.

Alzheimer Hastalığında Sinaptik İşlev Bozukluğu: Nöronal Değişimlere İlişkin Anlatımsal Bir Derleme

Abstract

Alzheimer hastalığı (AH), yaşlılar arasında yaygın bir nörolojik durum olup, ilerleyici bilişsel gerileme ile karakterize edilir ve en sık görülen demans türüdür. AH'nin belirgin patolojik özellikleri nörofibriler yumaklar (NFT'ler) ve amiloid beta (Aβ) plaklarıdır. Bununla birlikte, önemli deneysel kanıtlar, AH hastalarında bilişsel bozulmaya yol açan sinaptik fonksiyon değişikliklerinin, hastalığın erken belirtileri olabileceğini göstermektedir. Bu derlemede, AH'nin temelinde yatan pre- ve post-sinaptik yapı ve fonksiyondaki değişikliklerle ilgili ana bulguları sınıflandırıyor, tartışıyor ve açıklıyoruz. Aβ plakları ve NFT'ler tarafından neden olunan mekanik ve kimyasal bozukluklar, sinaptik fonksiyonu bozarak uzun süreli potansiyasyon (USP) ve uzun süreli depresyon (USD) süreçlerini zayıflatmakta ve pre- ve post-sinaptik proteinlerde değişikliklere yol açmaktadır.

Keywords

• Alzheimer hastalığı
• Pre-sinaptik yapılar
• Post-sinaptik yapılar
• Sinaptik işlev bozukluğu

References

1. Hippius H, Neundörfer G. The discovery of Alzheimer's disease. Dialogues Clin Neurosci. 2003;5(1):101-108.
2. Tarawneh R, Holtzman DM. The clinical problem of symptomatic Alzheimer disease and mild cognitive impairment. Cold Spring Harb Perspect Med. 2012;2(5):a006148.
3. Forner S, Baglietto-Vargas D, Martini AC, et al. Synaptic impairment in Alzheimer's disease: a dysregulated symphony. Trends Neurosci. 2017;40(6):347-357.
4. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-259.
5. Serrano-Pozo A, Frosch MP, Masliah E, et al. Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med. 2011;1(1):006189.
6. Zott B, Konnerth A. Impairments of glutamatergic synaptic transmission in Alzheimer’s disease. Semin Cell Dev Biol. 2022;S1084-9521(22):00080-5.
7. Fu WY, Ip NY. The role of genetic risk factors of Alzheimer’s disease in synaptic dysfunction. Semin Cell Dev Biol. 2023;139:3-12.
8. Terry RD, Masliah E, Salmon DP, et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30(4):572-580.

9. DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990;27(5):457-464.
10. Scheff SW, Price DA, Schmitt FA, et al. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology. 2007;68(18):1501-1508.
11. de Wilde MC, Overk CR, Sijben JW, et al. Meta-analysis of synaptic pathology in Alzheimer's disease reveals selective molecular vesicular machinery vulnerability. Alzheimers Dement. 2016;12(6):633-644.
12. Chen Y, Fu AKY, Ip NY. Synaptic dysfunction in Alzheimer's disease: Mechanisms and therapeutic strategies. Pharmacol Ther. 2019;195:186-198.
13. Tracy TE, Sohn PD, Minami SS, et al. Acetylated tau obstructs KIBRA-mediated signaling in synaptic plasticity and promotes tauopathy-related memory loss. Neuron. 2016;90(2):245-260.
14. Masliah E, Hansen L, Albright T, et al. Immunoelectron microscopic study of synaptic pathology in Alzheimer's disease. Acta Neuropathol. 1991;81:428-433.
15. Zhou ZD, Chan CH, Ma QH, et al. The roles of amyloid precursor protein (APP) in neurogenesis: Implications to pathogenesis and therapy of Alzheimer disease. Cell Adhes Migr. 2011;5(4):280-292.
16. Tang BL. Amyloid precursor protein (APP) and GABAergic neurotransmission. Cells. 2019;8(6):550.
17. Opsomer R, Contino S, Perrin F, et al. Amyloid Precursor Protein (APP) controls the expression of the transcriptional activator Neuronal PAS Domain Protein 4 (NPAS4) and synaptic GABA release. Eneuro. 2020;7(3).
18. D’Amore JD, Kajdasz ST, McLellan ME, et al. In vivo multiphoton imaging of a transgenic mouse model of Alzheimer disease reveals marked thioflavine-S-associated alterations in neurite trajectories. J Neuropathol Exp Neurol. 2003;62:137-145.
19. Schmid LC, Mittag M, Poll S, et al. Dysfunction of somatostatin-positive interneurons associated with memory deficits in an Alzheimer’s disease model. Neuron. 2016;92(1):114-125.
20. Blazquez-Llorca L, Valero-Freitag S, Rodrigues EF, et al. High plasticity of axonal pathology in Alzheimer's disease mouse models. Acta Neuropathol Commun. 2017;5(1):14.
21. Peters F, Salihoglu H, Rodrigues E, et al. BACE1 inhibition more effectively suppresses initiation than progression of beta-amyloid pathology. Acta Neuropathol. 2018;135:695-710.
22. Tsai J, Grutzendler J, Duff K, et al. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci. 2004;7:1181-1183.
23. Holtmaat A, Svoboda K. Experience-dependent structural synaptic plasticity in the mammalian brain. Nat Rev Neurosci. 2009;10:647-658.
24. Spires TL, Meyer-Luehmann M, Stern EA, et al. Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci. 2005;25:7278-7287.
25. Guptarak J, Scaduto P, Tumurbaatar B, et al. Cognitive integrity in Non-Demented Individuals with Alzheimer's Neuropathology is associated with preservation and remodeling of dendritic spines. Alzheimers Dement. 2024;20(7):4677-4691.
26. Zou C, Montagna E, Shi Y, et al. Intraneuronal APP and extracellular Abeta independently cause dendritic spine pathology in transgenic mouse models of Alzheimer's disease. Acta Neuropathol. 2015;129:909-920.
27. Mucke L, Masliah E, Yu GQ, et al. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci. 2000;20:4050-4058.
28. Ilina A, Linkova N. A Transgenic 5xFAD-M Line of Mice for Dendritic Spine Morphology Analysis in Alzheimer’s Disease. Brain Sci. 2023;13(2):307.
29. Sutton MA, Schuman EM. Dendritic protein synthesis, synaptic plasticity, and memory. Cell. 2006;127(1):49-58. 30. Malenka RC, Bear MF. LTP and LTD: An embarrassment of riches. Neuron. 2004;44(1):5-21.
30. Cullen WK, Suh YH, Anwyl R, et al. Block of LTP in rat hippocampus in vivo by beta-amyloid precursor protein fragments. Neuroreport. 1997;8:3213–3217.
31. Kim JH, Anwyl R, Suh YH, et al. Use-dependent effects of amyloidogenic fragments of (beta)-amyloid precursor protein on synaptic plasticity in rat hippocampus in vivo. J Neurosci. 2001;21:1327–1333.
32. Knobloch M, Farinelli M, Konietzko U, et al. Ab oligomer-mediated long-term potentiation impairment involves protein phosphatase 1-dependent mechanisms. J Neurosci. 2007;27:7648–7653.
33. Vintém AP, Henriques AG, da Cruz E Silva OA, et al. PP1 inhibition by Abeta peptide as a potential pathological mechanism in Alzheimer's disease. Neurotoxicol Teratol. 2009;31(2):85-8.
34. Shughrue PJ, Acton PJ, Breese RS, et al. Anti-ADDL antibodies differentially block oligomer binding to hippocampal neurons. Neurobiol Aging. 2010;31(2):189-202.
35. Lacor PN, Buniel MC, Furlow PW, et al. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci. 2007;27(4):796-807.
36. Dunys J, Valverde A, Checler F. Are N- and C-terminally truncated Aβ species key pathological triggers in Alzheimer's disease? J Biol Chem. 2018;293(40):15419–15428.
37. Wang Z, Jackson RJ, Hong W, et al. Human brain-derived Abeta oligomers bind to synapses and disrupt synaptic activity in a manner that requires APP. J Neurosci. 2017;37:11947–11966.
38. Hu NW, Corbett GT, Moore S, et al. Extracellular forms of Aβ and tau from iPSC models of Alzheimer's disease disrupt synaptic plasticity. Cell Rep. 2018;23:1932–1938.
39. Paula-Lima AC, Brito-Moreira J, Ferreira ST. Deregulation of excitatory neurotransmission underlying synapse failure in Alzheimer's disease. J Neurochem. 2013;126(2):191-202.
40. Barbier P, Zejneli O, Martinho M, et al. Role of Tau as a Microtubule-Associated Protein: Structural and Functional Aspects. Front Aging Neurosci. 2019;11:204.
41. Martin L, Latypova X, Wilson CM, et al.Tau protein phosphatases in Alzheimer’s disease: The leading role of PP2A. Ageing Res Rev. 2013;12:39–49.
42. Zhang B, Maiti A, Shively S, et al. Microtubule-Binding Drugs Offset Tau Sequestration by Stabilizing Microtubules and Reversing Fast Axonal Transport Deficits in a Tauopathy Model. Proc Natl Acad Sci USA. 2004;102:227–231.
43. Hoover BR, Reed MN, Su J, et al. Tau Mislocalization to Dendritic Spines Mediates Synaptic Dysfunction Independently of Neurodegeneration. Neuron. 2010;68:1067–1081.
44. Callahan LM, Vaules WA, Coleman PD. Quantitative decrease in synaptophysin message expression and increase in cathepsin D message expression in Alzheimer disease neurons containing neurofibrillary tangles. J Neuropathol Exp Neurol. 1999;58:275–287.
45. García-Escudero V, Gargini R, Martín-Maestro P, et al. Tau mRNA 3'UTR-to-CDS ratio is increased in Alzheimer disease. Neurosci Lett. 2017;655:101–108.
46. Mocanu MM, Nissen A, Eckermann K, et al. The potential for beta-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy. J Neurosci. 2008;28:737–748.
47. Busche MA, Wegmann S, Dujardin S, et al. Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo. Nat Neurosci. 2019;22:57–64.
48. Takamori S, Holt M, Stenius K, et al. Molecular anatomy of a trafficking organelle. Cell. 2006;127:831–846.
49. McInnes J, Wierda K, Snellinx A, et al. Synaptogyrin-3 mediates presynaptic dysfunction induced by tau. Neuron. 2018;97:823–835.e8.
50. Ittner A, Ittner LM. Dendritic tau in Alzheimer’s disease. Neuron. 2018;99:13-27.
51. Frandemiche ML, De Seranno S, Rush T, et al. Activity-Dependent tau protein translocation to excitatory synapse is disrupted by exposure to amyloid-beta oligomers. J Neurosci. 2014;34:6084-6097.
52. Thies E, Mandelkow E-M. Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1. J Neurosci. 2007;27:2896-2907.
53. Ittner LM, Ke YD, Delerue F, et al. Dendritic function of tau mediates amyloid-β toxicity in Alzheimer’s disease mouse models. Cell. 2010;142:387-397.
54. Bories C, Arsenault D, Lemire M, et al.Transgenic autoinhibition of p21-activated kinase exacerbates synaptic impairments and fronto-dependent behavioral deficits in an animal model of Alzheimer’s disease. Aging. 2017;9:1386-1403.
55. Liazoghli D, Perreault S, Micheva KD, et al.Fragmentation of the Golgi apparatus induced by the overexpression of wild-type and mutant human tau forms in neurons. Am J Pathol. 2005;166:1499-1514.
56. Lin WL, Lewis J, Yen SH, et al.Ultrastructural neuronal pathology in transgenic mice expressing mutant (P301L) human tau. J Neurocytol. 2003;32:1091-1105.
57. Lagalwar S, Berry RW, Binder LI. Relation of hippocampal phospho-SAPK/JNK granules in Alzheimer's disease and tauopathies to granulovacuolar degeneration bodies. Acta Neuropathol. 2007;113:63-73.
58. Nelson PT, Alafuzoff I, Bigio EH, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71(5):362-381.
59. Mucke L, Selkoe DJ. Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med. 2012;2(7):a006338.
60. Koss DJ, Jones G, Cranston A, et al. Soluble pre-fibrillar tau and β-amyloid species emerge in early human Alzheimer's disease and track disease progression and cognitive decline. Acta Neuropathol. 2016;132(6):875-895.
61. Koch G, Di Lorenzo F, Del Olmo MF, et al. Reversal of LTP-like cortical plasticity in Alzheimer's disease patients with tau-related faster clinical progression. J Alzheimers Dis. 2016;50(2):605-616.
62. Kimura T, Whitcomb DJ, Jo J, et al. Microtubule-associated protein tau is essential for long-term depression in the hippocampus. Philos Trans R Soc Lond B Biol Sci. 2014;369:20130144.
63. Peineau S, Taghibiglou C, Bradley C, et al. LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron. 2007;53(5):703-717.
64. Regan P, Piers T, Yi JH, et al. Tau phosphorylation at serine 396 residue is required for hippocampal LTD. J Neurosci. 2015;35(12):4804-4812.
65. Chen X-Q, Zuo X, Becker A, et al. Reduced synaptic proteins and SNARE complexes in Down syndrome with Alzheimer's disease and the Dp16 mouse Down syndrome model: Impact of APP gene dose. Alzheimer's Dement. 2023;19:2095-2116.
66. Verret L, Mann EO, Hang GB, et al. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell. 2012;149(3):708-721.
67. Sollner T, Whiteheart SW, Brunner M, et al. SNAP receptors implicated in vesicle targeting and fusion. Nature. 1993;362:318-324.
68. Jeans AF, Oliver PL, Johnson R, et al. A dominant mutation in Snap25 causes impaired vesicle trafficking, sensorimotor gating, and ataxia in the blind-drunk mouse. Proc Natl Acad Sci U S A. 2007;104:2431-2436.
69. Brinkmalm A, Brinkmalm G, Honer WG, et al.Targeting synaptic pathology with a novel affinity mass spectrometry approach. Mol Cell Proteomics. 2014;13(10):2584-2592.
70. Andreyeva A, Nieweg K, Horstmann K, et al. C-terminal fragment of N-cadherin accelerates synapse destabilization by amyloid-beta. Brain. 2012;135:2140–54.
71. Choi JY, Cho SJ, Park JH, et al. Elevated cerebrospinal fluid and plasma N-cadherin in Alzheimer disease. J Neuropathol Exp Neurol. 2020;79(5):484-492.
72. Brito-Moreira J, Lourenco MV, Oliveira MM, et al. Interaction of amyloid-β (Aβ) oligomers with neurexin 2α and neuroligin 1 mediates synapse damage and memory loss in mice. J Biol Chem. 2017;292:7327–7337.
73. Naito Y, Tanabe Y, Lee AK, et al. Amyloid-β oligomers interact with neurexin and diminish neurexin-mediated excitatory presynaptic organization. Sci Rep. 2017;7:42548.
74. Hishimoto A, Pletnikova O, Lang DL, et al. Neurexin 3 transmembrane and soluble isoform expression and splicing haplotype are associated with neuron inflammasome and Alzheimer's disease. Alzheimers Res Ther. 2019;11(1):28.
75. Anschuetz A, Schwab K, Harrington CR, et al. A meta-analysis on presynaptic changes in Alzheimer's disease. J Alzheimers Dis. 2024;97(1):145-162.
76. Song JY, Ichtchenko K, Südhof TC, et al. Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. Proc Natl Acad Sci U S A. 1999;96:1100–1105.
77. Bie B, Wu J, Yang H, et al. Epigenetic suppression of neuroligin 1 underlies amyloid-induced memory deficiency. Nat Neurosci. 2014;17:223–231.
78. Goetzl EJ, Abner EL, Jicha GA, et al. Declining levels of functionally specialized synaptic proteins in plasma neuronal exosomes with progression of Alzheimer’s disease. FASEB J. 2018;32:888–893.
79. Camporesi E, Lashley T, Gobom J, et al. Neuroligin-1 in brain and CSF of neurodegenerative disorders: investigation for synaptic biomarkers. Acta Neuropathol Commun. 2021;9:19.
80. Sheng M, Kim MJ. Postsynaptic signaling and plasticity mechanisms. Science. 2002;298(5594):776–780.
81. Savioz A, Leuba G, Vallet PG. A framework to understand the variations of PSD-95 expression in brain aging and in Alzheimer's disease. Ageing Res Rev. 2014;18:86–94.
82. Shao CY, Mirra SS, Sait HB, et al. Postsynaptic degeneration as revealed by PSD-95 reduction occurs after advanced Aβ and tau pathology in transgenic mouse models of Alzheimer’s disease. Acta Neuropathol. 2011;122(3):285-292.
83. Gylys KH, Fein JA, Yang F, et al. Synaptic changes in Alzheimer's disease: increased amyloid-β and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence. Am J Pathol. 2004;165(5):1809-1817.
84. Leuba G, Walzer C, Vernay A, et al. Postsynaptic density protein PSD-95 expression in Alzheimer's disease and okadaic acid induced neuritic retraction. Neurobiol Dis. 2008;30(3):408-419.
85. Xiao B, Tu JC, Petralia RS, et al. Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins. Neuron. 1998;21(4):707–716.
86. Roselli F, Hutzler P, Wegerich Y, et al. Disassembly of Shank and Homer synaptic clusters is driven by soluble β-amyloid1-40 through divergent NMDAR-dependent signalling pathways. PLoS ONE. 2009;4(6):e6011.
87. Kammermeier PJ. Surface clustering of metabotropic glutamate receptor 1 induced by long Homer proteins. BMC Neurosci. 2006;7:1.
88. Parisiadou L, Bethani I, Michaki V, et al. Homer2 and Homer3 interact with amyloid precursor protein and inhibit Aβ production. Neurobiol Dis. 2008;30:353–364.
89. Kivisäkk P, Carlyle BC, Sweeney T, et al. Increased levels of the synaptic proteins PSD-95, SNAP-25, and neurogranin in the cerebrospinal fluid of patients with Alzheimer's disease. Alzheimers Res Ther. 2022;14(1):58.
90. Lista S, Santos-Lozano A, Emanuele E, et al. Monitoring synaptic pathology in Alzheimer's disease through fluid and PET imaging biomarkers: a comprehensive review and future perspectives. Mol Psychiatry. 2024;29:847–857.
91. Kumar A, Scarpa M, Nordberg A. Tracing synaptic loss in Alzheimer's brain with SV2A PET-tracer UCB-J. Alzheimers Dement. 2024;20(4):2589–2605.
92. Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer's disease. J Cell Biol. 2018;217:459–472.
93. Rodríguez-Giraldo M, González-Reyes RE, Ramírez-Guerrero S, et al. Astrocytes as a therapeutic target in Alzheimer's disease—comprehensive review and recent developments. Int J Mol Sci. 2022;23(21):13630.