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Synaptic degeneration in Alzheimer disease

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From Nature Reviews Neurology

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Abstract

Alzheimer disease (AD) is characterized by progressive cognitive decline in older individuals accompanied by the presence of two pathological protein aggregates — amyloid-β and phosphorylated tau — in the brain. The disease results in brain atrophy caused by neuronal loss and synapse degeneration. Synaptic loss strongly correlates with cognitive decline in both humans and animal models of AD. Indeed, evidence suggests that soluble forms of amyloid-β and tau can cause synaptotoxicity and spread through neural circuits. These pathological changes are accompanied by an altered phenotype in the glial cells of the brain — one hypothesis is that glia excessively ingest synapses and modulate the trans-synaptic spread of pathology. To date, effective therapies for the treatment or prevention of AD are lacking, but understanding how synaptic degeneration occurs will be essential for the development of new interventions. Here, we highlight the mechanisms through which synapses degenerate in the AD brain, and discuss key questions that still need to be answered. We also cover the ways in which our understanding of the mechanisms of synaptic degeneration is leading to new therapeutic approaches for AD.

Key points

  • Synaptic degeneration is a prominent feature of Alzheimer disease (AD) both in humans and in preclinical models of the disease.

  • Evidence indicates that synaptic degeneration is the best neuropathological correlate of cognitive decline in AD; however, effective treatments to slow down or stop synaptic loss are lacking.

  • Amyloid-β (Aβ) and tau are the most well-studied contributors to synaptic degeneration in AD and, although most anti-Aβ therapies have so far failed in clinical trials, targeting these proteins earlier in the disease process might ameliorate neurodegeneration.

  • Microglia and astrocytes can drive synaptic degeneration in animal models of ageing and AD via ingestion of tagged synapses, contributing to cognitive decline.

  • Many clinical trials are now focusing on the interactions between immune responses and neurons in AD, as opposed to focusing only on the reduction of Aβ and tau levels.

  • New synaptic biomarkers are being developed with the aim of aiding the earlier diagnosis of AD and distinguishing between people who will stay cognitively healthy as they age and people who will develop AD.

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Fig. 1: Interlinking mechanisms of synaptic degeneration by neuropathological proteins and glial reactivity.
Fig. 2: Putative mechanisms of synaptic degeneration by Aβ and tau in Alzheimer disease.
Fig. 3: The tripartite synapse and candidate ‘eat-me’ signals in Alzheimer disease.
Fig. 4: Synaptic biomarkers in Alzheimer disease.

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References

  1. WHO. Global action plan on the public health response to dementia 2017–2025 (WHO, 2017).

  2. Spires-Jones, T. L. Alzheimer’s research – breakthrough or breakdown? Brain Commun. 3, fcab217 (2021).

    Article  Google Scholar 

  3. Biogen. Lecanemab confirmatory phase 3 CLARITY AD study met primary endpoubt, showing highly statistically significant reduction of clinical decline in large global clinical study of 1,795 participants with early Alzheimer’s disease. Biogen https://investors.biogen.com/news-releases/news-release-details/lecanemab-confirmatory-phase-3-clarity-ad-study-met-primary (2022).

  4. DeKosky, S. T. & Scheff, S. W. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann. Neurol. 27, 457–464 (1990).

    Article  CAS  Google Scholar 

  5. Terry, R. D. et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572–580 (1991).

    Article  CAS  Google Scholar 

  6. Mecca, A. P. et al. Synaptic density and cognitive performance in Alzheimer’s disease: a PET imaging study with [11C]UCB-J. Alzheimers Dement. https://doi.org/10.1002/alz.12582 (2022).

    Article  Google Scholar 

  7. Kopeikina, K. J., Hyman, B. T. & Spires-Jones, T. L. Soluble forms of tau are toxic in Alzheimer’s disease. Transl Neurosci. 3, 223–233 (2012).

    Article  Google Scholar 

  8. Spires-Jones, T. L. & Hyman, B. T. The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron 82, 756–771 (2014).

    Article  CAS  Google Scholar 

  9. Polydoro, M. et al. Soluble pathological tau in the entorhinal cortex leads to presynaptic deficits in an early Alzheimer’s disease model. Acta Neuropathol. 127, 257–270 (2014).

    Article  CAS  Google Scholar 

  10. Fá, M. et al. Extracellular tau oligomers produce an immediate impairment of LTP and memory. Sci. Rep. 6, 19393 (2016).

    Article  Google Scholar 

  11. Shankar, G. M. et al. Amyloid-β protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat. Med. 14, 837–842 (2008).

    Article  CAS  Google Scholar 

  12. Hong, W. et al. Diffusible, highly bioactive oligomers represent a critical minority of soluble Aβ in Alzheimer’s disease brain. Acta Neuropathol. 136, 19–40 (2018).

    Article  CAS  Google Scholar 

  13. Klein, W. L. Synaptotoxic amyloid-β oligomers: a molecular basis for the cause, diagnosis, and treatment of Alzheimer’s disease? J. Alzheimers Dis. 33, S49–S65 (2013).

    Article  Google Scholar 

  14. Perez-Nievas, B. G. et al. Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology. Brain 136, 2510–2526 (2013).

    Article  Google Scholar 

  15. Mc Donald, J. M. et al. The presence of sodium dodecyl sulphate-stable Aβ dimers is strongly associated with Alzheimer-type dementia. Brain 133, 1328–1341 (2010).

    Article  Google Scholar 

  16. de Calignon, A. et al. Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73, 685–697 (2012).

    Article  Google Scholar 

  17. Pickett, E. K. et al. Spread of tau down neural circuits precedes synapse and neuronal loss in the rTgTauEC mouse model of early Alzheimer’s disease. Synapse 71, e21965 (2017).

    Article  Google Scholar 

  18. Jucker, M. & Walker, L. C. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45–51 (2013).

    Article  CAS  Google Scholar 

  19. d’Errico, P. & Meyer-Luehmann, M. Mechanisms of pathogenic tau and Aβ protein spreading in Alzheimer’s disease. Front. Aging Neurosci. 12, 265 (2020).

    Article  Google Scholar 

  20. Takeda, S. et al. Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain. Nat. Commun. 6, 8490 (2015).

    Article  CAS  Google Scholar 

  21. Pooler, A. M., Phillips, E. C., Lau, D. H. W., Noble, W. & Hanger, D. P. Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep. 14, 389–394 (2013).

    Article  CAS  Google Scholar 

  22. Yamada, K. et al. Neuronal activity regulates extracellular tau in vivo. J. Exp. Med. 211, 387–393 (2014).

    Article  CAS  Google Scholar 

  23. Cirrito, J. R. et al. Endocytosis is required for synaptic activity-dependent release of amyloid-β in vivo. Neuron 58, 42–51 (2008).

    Article  CAS  Google Scholar 

  24. Harris, J. A. et al. Human P301L-mutant tau expression in mouse entorhinal-hippocampal network causes tau aggregation and presynaptic pathology but no cognitive deficits. PLoS ONE 7, e45881 (2012).

    Article  CAS  Google Scholar 

  25. Liu, L. et al. Trans-synaptic spread of tau pathology in vivo. PLoS ONE 7, e31302 (2012).

    Article  CAS  Google Scholar 

  26. Wegmann, S. et al. Experimental evidence for the age dependence of tau protein spread in the brain. Sci. Adv. 5, eaaw6404 (2019).

    Article  CAS  Google Scholar 

  27. Henstridge, C. M., Hyman, B. T. & Spires-Jones, T. L. Beyond the neuron-cellular interactions early in Alzheimer disease pathogenesis. Nat. Rev. Neurosci. 20, 94–108 (2019).

    Article  CAS  Google Scholar 

  28. De Strooper, B. & Karran, E. The cellular phase of Alzheimer’s disease. Cell 164, 603–615 (2016).

    Article  Google Scholar 

  29. Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017).

    Article  CAS  Google Scholar 

  30. Habib, N. et al. Disease-associated astrocytes in Alzheimer’s disease and aging. Nat. Neurosci. 23, 701–706 (2020).

    Article  CAS  Google Scholar 

  31. Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 (2013).

    Article  CAS  Google Scholar 

  32. Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013).

    Article  CAS  Google Scholar 

  33. Strittmatter, W. J. & Roses, A. D. Apolipoprotein E and Alzheimer’s disease. Annu. Rev. Neurosci. 19, 53–77 (1996).

    Article  CAS  Google Scholar 

  34. Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017).

    Article  CAS  Google Scholar 

  35. Kent, S. A., Spires-Jones, T. L. & Durrant, C. S. The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics. Acta Neuropathol. 140, 417–447 (2020).

    Article  CAS  Google Scholar 

  36. Hardy, J. A. & Higgins, G. A. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).

    Article  CAS  Google Scholar 

  37. Hardy, J. The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal. J. Neurochem. 110, 1129–1134 (2009).

    Article  CAS  Google Scholar 

  38. O’Brien, R. J. & Wong, P. C. Amyloid precursor protein processing and Alzheimer’s disease. Annu. Rev. Neurosci. 34, 185–204 (2011).

    Article  Google Scholar 

  39. Cole, S. L. & Vassar, R. The Alzheimer’s disease β-secretase enzyme, BACE1. Mol. Neurodegener. 2, 22 (2007).

    Article  Google Scholar 

  40. Richter, M. C. et al. Distinct in vivo roles of secreted APP ectodomain variants APPsα and APPsβ in regulation of spine density, synaptic plasticity, and cognition. EMBO J. 37, e98335 (2018).

    Article  Google Scholar 

  41. Kuhn, P.-H. et al. ADAM10 is the physiologically relevant, constitutive α-secretase of the amyloid precursor protein in primary neurons. EMBO J. 29, 3020–3032 (2010).

    Article  CAS  Google Scholar 

  42. Jackson, R. J. et al. Clusterin accumulates in synapses in Alzheimer’s disease and is increased in apolipoprotein E4 carriers. Brain Commun. 1, fcz003 (2019).

    Article  Google Scholar 

  43. Koffie, R. M. et al. Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β. Brain 135, 2155–2168 (2012).

    Article  Google Scholar 

  44. Pickett, E. K. et al. Amyloid beta and tau cooperate to cause reversible behavioral and transcriptional deficits in a model of Alzheimer’s disease. Cell Rep. 29, 3592–3604.e5 (2019).

    Article  CAS  Google Scholar 

  45. Koffie, R. M. et al. Oligomeric amyloid associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc. Natl Acad. Sci. USA 106, 4012–4017 (2009).

    Article  CAS  Google Scholar 

  46. Fein, J. A. et al. Co-localization of amyloid beta and tau pathology in Alzheimer’s disease synaptosomes. Am. J. Pathol. 172, 1683–1692 (2008).

    Article  CAS  Google Scholar 

  47. Tai, H.-C. et al. The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am. J. Pathol. 181, 1426–1435 (2012).

    Article  CAS  Google Scholar 

  48. Paspalas, C. D. et al. The aged rhesus macaque manifests Braak stage III/IV Alzheimer’s-like pathology. Alzheimers Dement. 14, 680–691 (2018).

    Article  Google Scholar 

  49. Hoover, B. R. et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68, 1067–1081 (2010).

    Article  CAS  Google Scholar 

  50. Kopeikina, K. J. et al. Synaptic alterations in the rTg4510 mouse model of tauopathy. J. Comp. Neurol. 521, 1334–1353 (2013).

    Article  CAS  Google Scholar 

  51. Zhou, L. et al. Tau association with synaptic vesicles causes presynaptic dysfunction. Nat. Commun. 8, 15295 (2017).

    Article  Google Scholar 

  52. Rozkalne, A., Spires-Jones, T. L., Stern, E. A. & Hyman, B. T. A single dose of passive immunotherapy has extended benefits on synapses and neurites in an Alzheimer’s disease mouse model. Brain Res. 1280, 178–185 (2009).

    Article  CAS  Google Scholar 

  53. Spires-Jones, T. L. et al. Passive immunotherapy rapidly increases structural plasticity in a mouse model of Alzheimer disease. Neurobiol. Dis. 33, 213–220 (2009).

    Article  CAS  Google Scholar 

  54. Sydow, A. et al. Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic tau mutant. J. Neurosci. 31, 2511–2525 (2011).

    Article  CAS  Google Scholar 

  55. Roberson, E. D. et al. Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer’s disease. J. Neurosci. 31, 700–711 (2011).

    Article  CAS  Google Scholar 

  56. Roberson, E. D. et al. Reducing endogenous tau ameliorates amyloid-induced deficits in an Alzheimer’s disease mouse model. Science 316, 750–754 (2007).

    Article  CAS  Google Scholar 

  57. Shankar, G. M. et al. Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J. Neurosci. 27, 2866–2875 (2007).

    Article  CAS  Google Scholar 

  58. Townsend, M., Shankar, G. M., Mehta, T., Walsh, D. M. & Selkoe, D. J. Effects of secreted oligomers of amyloid β-protein on hippocampal synaptic plasticity: a potent role for trimers. J. Physiol. 572, 477–492 (2006).

    Article  CAS  Google Scholar 

  59. Walsh, D. M. et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 (2002).

    Article  CAS  Google Scholar 

  60. Cleary, J. P. et al. Natural oligomers of the amyloid-β protein specifically disrupt cognitive function. Nat. Neurosci. 8, 79–84 (2005).

    Article  CAS  Google Scholar 

  61. Walsh, D. M. et al. The role of cell-derived oligomers of Abeta in Alzheimer’s disease and avenues for therapeutic intervention. Biochem. Soc. Trans. 33, 1087–1090 (2005).

    Article  CAS  Google Scholar 

  62. Beckman, D. et al. Oligomeric Aβ in the monkey brain impacts synaptic integrity and induces accelerated cortical aging. Proc. Natl Acad. Sci. USA 116, 26239–26246 (2019).

    Article  CAS  Google Scholar 

  63. Acquarone, E. et al. Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade. Mol. Neurodegener. 14, 26 (2019).

    Article  Google Scholar 

  64. Kaniyappan, S., Chandupatla, R. R., Mandelkow, E.-M. & Mandelkow, E. Extracellular low-n oligomers of tau cause selective synaptotoxicity without affecting cell viability. Alzheimers Dement. 13, 1270–1291 (2017).

    Article  Google Scholar 

  65. Decker, J. M. et al. Pro-aggregant Tau impairs mossy fiber plasticity due to structural changes and Ca(++) dysregulation. Acta Neuropathol. Commun. 3, 23 (2015).

    Article  Google Scholar 

  66. Moreno, H. et al. Tau pathology-mediated presynaptic dysfunction. Neuroscience 325, 30–38 (2016).

    Article  CAS  Google Scholar 

  67. Lacor, P. N. et al. Synaptic targeting by Alzheimer’s-related amyloid β oligomers. J. Neurosci. 24, 10191–10200 (2004).

    Article  CAS  Google Scholar 

  68. Laurén, J., Gimbel, D. A., Nygaard, H. B., Gilbert, J. W. & Strittmatter, S. M. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers. Nature 457, 1128–1132 (2009).

    Article  Google Scholar 

  69. Renner, M. et al. Deleterious effects of amyloid β oligomers acting as an extracellular scaffold for mGluR5. Neuron 66, 739–754 (2010).

    Article  CAS  Google Scholar 

  70. Barry, A. E. et al. Alzheimer’s disease brain-derived amyloid-β-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein. J. Neurosci. 31, 7259–7263 (2011).

    Article  CAS  Google Scholar 

  71. Hu, N.-W. et al. mGlu5 receptors and cellular prion protein mediate amyloid-β-facilitated synaptic long-term depression in vivo. Nat. Commun. 5, 3374 (2014).

    Article  Google Scholar 

  72. Zhang, D. et al. Targeting glutamatergic and cellular prion protein mechanisms of amyloid β-mediated persistent synaptic plasticity disruption: longitudinal studies. Neuropharmacology 121, 231–246 (2017).

    Article  CAS  Google Scholar 

  73. Um, J. W. et al. Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer Aβ oligomer bound to cellular prion protein. Neuron 79, 887–902 (2013).

    Article  CAS  Google Scholar 

  74. Larson, M. et al. The complex PrP(c)-Fyn couples human oligomeric Aβ with pathological tau changes in Alzheimer’s disease. J. Neurosci. 32, 16857–16871 (2012).

    Article  CAS  Google Scholar 

  75. Salazar, S. V. et al. Conditional deletion of Prnp rescues behavioral and synaptic deficits after disease onset in transgenic Alzheimer’s disease. J. Neurosci. 37, 9207–9221 (2017).

    Article  CAS  Google Scholar 

  76. Kaufman, A. C. et al. Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. Ann. Neurol. 77, 953–971 (2015).

    Article  CAS  Google Scholar 

  77. van Dyck, C. H. et al. Effect of AZD0530 on cerebral metabolic decline in Alzheimer disease: a randomized clinical trial. JAMA Neurol. 76, 1219–1229 (2019).

    Article  Google Scholar 

  78. Folch, J. et al. Memantine for the treatment of dementia: a review on its current and future applications. J. Alzheimers Dis. 62, 1223–1240 (2018).

    Article  CAS  Google Scholar 

  79. Gunn, A. P. et al. Amyloid-β peptide Aβ3pE-42 induces lipid peroxidation, membrane permeabilization, and calcium influx in neurons. J. Biol. Chem. 291, 6134–6145 (2016).

    Article  CAS  Google Scholar 

  80. Wei, W. et al. Amyloid beta from axons and dendrites reduces local spine number and plasticity. Nat. Neurosci. 13, 190–196 (2010).

    Article  CAS  Google Scholar 

  81. Fani, G. et al. Aβ oligomers dysregulate calcium homeostasis by mechanosensitive activation of AMPA and NMDA receptors. ACS Chem. Neurosci. 12, 766–781 (2021).

    Article  CAS  Google Scholar 

  82. Gomes, G. M. et al. Inhibition of the polyamine system counteracts β-amyloid peptide-induced memory impairment in mice: involvement of extrasynaptic NMDA receptors. PLoS ONE 9, e99184 (2014).

    Article  Google Scholar 

  83. Dieterich, D. C. et al. Caldendrin–Jacob: a protein liaison that couples NMDA receptor signalling to the nucleus. PLoS Biol. 6, e34 (2008).

    Article  Google Scholar 

  84. Rönicke, R. et al. Early neuronal dysfunction by amyloid β oligomers depends on activation of NR2B-containing NMDA receptors. Neurobiol. Aging 32, 2219–2228 (2011).

    Article  Google Scholar 

  85. Yin, Y. et al. Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling. Proc. Natl Acad. Sci. USA 113, E3773–E3781 (2016).

    Article  CAS  Google Scholar 

  86. McClendon, M. J., Hernandez, S., Smyth, K. A. & Lerner, A. J. Memantine and acetylcholinesterase inhibitor treatment in cases of CDR 0.5 or questionable impairment. J. Alzheimers Dis. 16, 577–583 (2009).

    Article  CAS  Google Scholar 

  87. Wang, H.-F. et al. Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in Parkinson’s disease, Parkinson’s disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and trial sequential analysis. J. Neurol. Neurosurg. Psychiatry 86, 135–143 (2015).

    Article  Google Scholar 

  88. Cissé, M. et al. Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature 469, 47–52 (2011).

    Article  Google Scholar 

  89. Ohnishi, T. et al. Na,K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly. Proc. Natl Acad. Sci. USA 112, E4465–E4474 (2015).

    Article  CAS  Google Scholar 

  90. Magdesian, M. H. et al. Amyloid-β binds to the extracellular cysteine-rich domain of Frizzled and inhibits Wnt/β-catenin signaling. J. Biol. Chem. 283, 9359–9368 (2008).

    Article  CAS  Google Scholar 

  91. Zhao, W.-Q. et al. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 22, 246–260 (2008).

    Article  CAS  Google Scholar 

  92. Costantini, C. et al. Characterization of the signaling pathway downstream p75 neurotrophin receptor involved in β-amyloid peptide-dependent cell death. J. Mol. Neurosci. 25, 141–156 (2005).

    Article  CAS  Google Scholar 

  93. Yamamoto, N. et al. A ganglioside-induced toxic soluble Aβ assembly. Its enhanced formation from Aβ bearing the Arctic mutation. J. Biol. Chem. 282, 2646–2655 (2007).

    Article  CAS  Google Scholar 

  94. Riad, A. et al. The sigma-2 receptor/TMEM97, PGRMC1, and LDL receptor complex are responsible for the cellular uptake of Aβ42 and its protein aggregates. Mol. Neurobiol. 57, 3803–3813 (2020).

    Article  CAS  Google Scholar 

  95. Izzo, N. J. et al. Alzheimer’s therapeutics targeting amyloid beta 1-42 oligomers II: sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity. PLoS ONE 9, e111899 (2014).

    Article  Google Scholar 

  96. Marcello, E. et al. Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer’s disease. J. Clin. Invest. 123, 2523–2538 (2013).

    Article  CAS  Google Scholar 

  97. Musardo, S. et al. The development of ADAM10 endocytosis inhibitors for the treatment of Alzheimer’s disease. Mol. Ther. 30, 2474–2490 (2022).

    Article  CAS  Google Scholar 

  98. Bold, C. S. et al. APPsα rescues tau-induced synaptic pathology. J. Neurosci. 42, 5782–5802 (2022).

    Article  CAS  Google Scholar 

  99. Gómez-Ramos, A., Díaz-Hernández, M., Rubio, A., Miras-Portugal, M. T. & Avila, J. Extracellular tau promotes intracellular calcium increase through M1 and M3 muscarinic receptors in neuronal cells. Mol. Cell Neurosci. 37, 673–681 (2008).

    Article  Google Scholar 

  100. McInnes, J. et al. Synaptogyrin-3 mediates presynaptic dysfunction induced by tau. Neuron 97, 823–835 (2018).

    Article  CAS  Google Scholar 

  101. Largo-Barrientos, P. et al. Lowering synaptogyrin-3 expression rescues Tau-induced memory defects and synaptic loss in the presence of microglial activation. Neuron 109, 767–777 (2021).

    Article  CAS  Google Scholar 

  102. Liu, C., Song, X., Nisbet, R. & Götz, J. Co-immunoprecipitation with tau isoform-specific antibodies reveals distinct protein interactions and highlights a putative role for 2N tau in disease. J. Biol. Chem. 291, 8173–8188 (2016).

    Article  CAS  Google Scholar 

  103. Lasagna-Reeves, C. A. et al. Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice. Mol. Neurodegener. 6, 39 (2011).

    Article  Google Scholar 

  104. Balaji, V., Kaniyappan, S., Mandelkow, E., Wang, Y. & Mandelkow, E.-M. Pathological missorting of endogenous MAPT/Tau in neurons caused by failure of protein degradation systems. Autophagy 14, 2139–2154 (2018).

    CAS  Google Scholar 

  105. Zhao, X. et al. Caspase-2 cleavage of tau reversibly impairs memory. Nat. Med. 22, 1268–1276 (2016).

    Article  CAS  Google Scholar 

  106. Ittner, L. M. et al. Dendritic function of tau mediates amyloid-β toxicity in Alzheimer’s disease mouse models. Cell 142, 387–397 (2010).

    Article  CAS  Google Scholar 

  107. Tang, S. J. et al. Fyn kinase inhibition reduces protein aggregation, increases synapse density and improves memory in transgenic and traumatic tauopathy. Acta Neuropathol. Commun. 8, 96 (2020).

    Article  CAS  Google Scholar 

  108. Zempel, H. et al. Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin. EMBO J. 32, 2920–2937 (2013).

    Article  CAS  Google Scholar 

  109. Busche, M. A. et al. Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 109, 8740–8745 (2012).

    Article  CAS  Google Scholar 

  110. Kuchibhotla, K. V. et al. Aβ plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron 59, 214–225 (2008).

    Article  CAS  Google Scholar 

  111. Arbel-Ornath, M. et al. Soluble oligomeric amyloid-β induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain. Mol. Neurodegener. 12, 27 (2017).

    Article  Google Scholar 

  112. Jang, H. et al. β-Barrel topology of Alzheimer’s β-amyloid ion channels. J. Mol. Biol. 404, 917–934 (2010).

    Article  CAS  Google Scholar 

  113. Kokubo, H. et al. Amyloid beta annular protofibrils in cell processes and synapses accumulate with aging and Alzheimer-associated genetic modification. Int. J. Alzheimers Dis. 2009, 689285 (2009).

    Google Scholar 

  114. Lal, R., Lin, H. & Quist, A. P. Amyloid beta ion channel: 3D structure and relevance to amyloid channel paradigm. Biochim. Biophys. Acta Biomembr. 1768, 1966–1975 (2007).

    Article  CAS  Google Scholar 

  115. Kayed, R. et al. Annular protofibrils are a structurally and functionally distinct type of amyloid oligomer. J. Biol. Chem. 284, 4230–4237 (2009).

    Article  CAS  Google Scholar 

  116. Halpain, S., Hipolito, A. & Saffer, L. Regulation of F-actin stability in dendritic spines by glutamate receptors and calcineurin. J. Neurosci. 18, 9835–9844 (1998).

    Article  CAS  Google Scholar 

  117. Wu, H.-Y. et al. Amyloid β induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J. Neurosci. 30, 2636–2649 (2010).

    Article  CAS  Google Scholar 

  118. Rozkalne, A., Hyman, B. T. & Spires-Jones, T. L. Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model mice. Neurobiol. Dis. 41, 650–654 (2011).

    Article  CAS  Google Scholar 

  119. Hesse, R. et al. Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype. Acta Neuropathol. Commun. 7, 214 (2019).

    Article  CAS  Google Scholar 

  120. Biasetti, L. et al. Elevated amyloid beta disrupts the nanoscale organization and function of synaptic vesicle pools in hippocampal neurons. Cereb. Cortex https://doi.org/10.1093/cercor/bhac134 (2022).

    Article  Google Scholar 

  121. Usenovic, M. et al. Internalized tau oligomers cause neurodegeneration by inducing accumulation of pathogenic tau in human neurons derived from induced pluripotent stem cells. J. Neurosci. 35, 14234–14250 (2015).

    Article  CAS  Google Scholar 

  122. Kopeikina, K. J. et al. Tau causes synapse loss without disrupting calcium homeostasis in the rTg4510 model of tauopathy. PLoS ONE 8, e80834 (2013).

    Article  Google Scholar 

  123. Kuchibhotla, K. V. et al. Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo. Proc. Natl Acad. Sci. USA 111, 510–514 (2014).

    Article  CAS  Google Scholar 

  124. Mattson, M. P. Calcium and neurodegeneration. Aging Cell 6, 337–350 (2007).

    Article  CAS  Google Scholar 

  125. Arnsten, A. F. T., Datta, D., Del Tredici, K. & Braak, H. Hypothesis: tau pathology is an initiating factor in sporadic Alzheimer’s disease. Alzheimers Dement. 17, 115–124 (2021).

    Article  CAS  Google Scholar 

  126. Datta, D. et al. Age-related calcium dysregulation linked with tau pathology and impaired cognition in non-human primates. Alzheimers Dement. 17, 920–932 (2021).

    Article  CAS  Google Scholar 

  127. Mattson, M. P., Gary, D. S., Chan, S. L. & Duan, W. Perturbed endoplasmic reticulum function, synaptic apoptosis and the pathogenesis of Alzheimer’s disease. Biochem. Soc. Symp. 67, 151–162 (2001).

    Article  CAS  Google Scholar 

  128. Adamec, E., Mohan, P., Vonsattel, J. P. & Nixon, R. A. Calpain activation in neurodegenerative diseases: confocal immunofluorescence study with antibodies specifically recognizing the active form of calpain 2. Acta Neuropathol. 104, 92–104 (2002).

    Article  CAS  Google Scholar 

  129. Jin, M. et al. Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc. Natl Acad. Sci. USA 108, 5819–5824 (2011).

    Article  CAS  Google Scholar 

  130. Busche, M. A. et al. Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo. Nat. Neurosci. 22, 57–64 (2019).

    Article  CAS  Google Scholar 

  131. Marinković, P. et al. In vivo imaging reveals reduced activity of neuronal circuits in a mouse tauopathy model. Brain 142, 1051–1062 (2019).

    Article  Google Scholar 

  132. Wu, Q. et al. Increased neuronal activity in motor cortex reveals prominent calcium dyshomeostasis in tauopathy mice. Neurobiol. Dis. 147, 105165 (2021).

    Article  CAS  Google Scholar 

  133. Cenini, G. & Voos, W. Mitochondria as potential targets in Alzheimer disease therapy: an update. Front. Pharmacol. 10, 902 (2019).

    Article  CAS  Google Scholar 

  134. Hauptmann, S. et al. Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol. Aging 30, 1574–1586 (2009).

    Article  CAS  Google Scholar 

  135. Bell, S. M. et al. Mitochondrial dysfunction in Alzheimer’s disease: a biomarker of the future? Biomedicines 9, 63 (2021).

    Article  CAS  Google Scholar 

  136. Xie, H. et al. Mitochondrial alterations near amyloid plaques in an Alzheimer’s disease mouse model. J. Neurosci. 33, 17042–17051 (2013).

    Article  CAS  Google Scholar 

  137. Pickett, E. K. et al. Region-specific depletion of synaptic mitochondria in the brains of patients with Alzheimer’s disease. Acta Neuropathol. 136, 747–757 (2018).

    Article  CAS  Google Scholar 

  138. Hansson Petersen, C. A. et al. The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc. Natl Acad. Sci. USA 105, 13145–13150 (2008).

    Article  CAS  Google Scholar 

  139. Hernandez-Zimbron, L. F. et al. Amyloid-β peptide binds to cytochrome c oxidase subunit 1. PLoS ONE 7, e42344 (2012).

    Article  CAS  Google Scholar 

  140. Lustbader, J. W. et al. ABAD directly links Aβ to mitochondrial toxicity in Alzheimer’s disease. Science 304, 448–452 (2004).

    Article  CAS  Google Scholar 

  141. Wang, X. et al. Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc. Natl Acad. Sci. USA 105, 19318–19323 (2008).

    Article  CAS  Google Scholar 

  142. Kopeikina, K. J. et al. Tau accumulation causes mitochondrial distribution deficits in neurons in a mouse model of tauopathy and in human Alzheimer’s disease brain. Am. J. Pathol. 179, 2071–2082 (2011).

    Article  CAS  Google Scholar 

  143. Manczak, M. & Reddy, P. H. Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer’s disease neurons: implications for mitochondrial dysfunction and neuronal damage. Hum. Mol. Genet. 21, 2538–2547 (2012).

    Article  CAS  Google Scholar 

  144. D’Amelio, M. et al. Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer’s disease. Nat. Neurosci. 14, 69–76 (2011).

    Article  Google Scholar 

  145. Park, G. et al. Caspase activation and caspase-mediated cleavage of APP is associated with amyloid β-protein-induced synapse loss in Alzheimer’s disease. Cell Rep. 31, 107839 (2020).

    Article  CAS  Google Scholar 

  146. Louneva, N. et al. Caspase-3 is enriched in postsynaptic densities and increased in Alzheimer’s disease. Am. J. Pathol. 173, 1488–1495 (2008).

    Article  CAS  Google Scholar 

  147. Baumgartner, H. K. et al. Calcium elevation in mitochondria is the main Ca2+ requirement for mitochondrial permeability transition pore (mPTP) opening. J. Biol. Chem. 284, 20796–20803 (2009).

    Article  CAS  Google Scholar 

  148. D’Amelio, M., Cavallucci, V. & Cecconi, F. Neuronal caspase-3 signaling: not only cell death. Cell Death Differ. 17, 1104–1114 (2010).

    Article  Google Scholar 

  149. Pérez, M. J., Vergara-Pulgar, K., Jara, C., Cabezas-Opazo, F. & Quintanilla, R. A. Caspase-cleaved tau impairs mitochondrial dynamics in Alzheimer’s disease. Mol. Neurobiol. 55, 1004–1018 (2018).

    Article  Google Scholar 

  150. Bertholet, A. M. et al. OPA1 loss of function affects in vitro neuronal maturation. Brain 136, 1518–1533 (2013).

    Article  Google Scholar 

  151. Bero, A. W. et al. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat. Neurosci. 14, 750–756 (2011).

    Article  CAS  Google Scholar 

  152. Jack, C. R. et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 12, 207–216 (2013).

    Article  CAS  Google Scholar 

  153. Tzioras, M., Davies, C., Newman, A., Jackson, R. & Spires-Jones, T. Invited review: APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer’s disease. Neuropathol. Appl. Neurobiol. 45, 327–346 (2019).

    Article  CAS  Google Scholar 

  154. Greicius, M. D., Srivastava, G., Reiss, A. L. & Menon, V. Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: evidence from functional MRI. Proc. Natl Acad. Sci. USA 101, 4637–4642 (2004).

    Article  CAS  Google Scholar 

  155. Hafkemeijer, A., van der Grond, J. & Rombouts, S. A. R. B. Imaging the default mode network in aging and dementia. Biochim. Biophys. Acta Mol. Basis Dis. 1822, 431–441 (2012).

    Article  CAS  Google Scholar 

  156. Badhwar, A. et al. Resting-state network dysfunction in Alzheimer’s disease: a systematic review and meta-analysis. Alzheimers Dement. 8, 73–85 (2017).

    Google Scholar 

  157. Mevel, K., Chételat, G., Eustache, F. & Desgranges, B. The default mode network in healthy aging and Alzheimer’s disease. Int. J. Alzheimers Dis. 2011, e535816 (2011).

    Google Scholar 

  158. Sperling, R. A. et al. Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron 63, 178–188 (2009).

    Article  CAS  Google Scholar 

  159. Palmqvist, S. et al. Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity. Nat. Commun. 8, 1214 (2017).

    Article  Google Scholar 

  160. Aloisi, F. Immune function of microglia. Glia 36, 165–179 (2001).

    Article  CAS  Google Scholar 

  161. Diaz-Aparicio, I. et al. Microglia actively remodel adult hippocampal neurogenesis through the phagocytosis secretome. J. Neurosci. 40, 1453–1482 (2020).

    Article  CAS  Google Scholar 

  162. Abbott, N. J., Rönnbäck, L. & Hansson, E. Astrocyte–endothelial interactions at the blood–brain barrier. Nat. Rev. Neurosci. 7, 41–53 (2006).

    Article  CAS  Google Scholar 

  163. Banker, G. A. Trophic interactions between astroglial cells and hippocampal neurons in culture. Science 209, 809–810 (1980).

    Article  CAS  Google Scholar 

  164. Li, X. et al. MEK is a key regulator of gliogenesis in the developing brain. Neuron 75, 1035–1050 (2012).

    Article  CAS  Google Scholar 

  165. Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).

    Article  CAS  Google Scholar 

  166. Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).

    Article  CAS  Google Scholar 

  167. Oosterhof, N. et al. Homozygous mutations in CSF1R cause a pediatric-onset leukoencephalopathy and can result in congenital absence of microglia. Am. J. Hum. Genet. 104, 936–947 (2019).

    Article  CAS  Google Scholar 

  168. Wu, T. et al. Complement C3 is activated in human AD brain and is required for neurodegeneration in mouse models of amyloidosis and tauopathy. Cell Rep. 28, 2111–2123 (2019).

    Article  CAS  Google Scholar 

  169. Chung, W.-S. et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504, 394–400 (2013).

    Article  CAS  Google Scholar 

  170. Scott-Hewitt, N. et al. Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia. EMBO J. 39, e105380 (2020).

    Article  CAS  Google Scholar 

  171. Vainchtein, I. D. et al. Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science 359, 1269–1273 (2018).

    Article  CAS  Google Scholar 

  172. Spurrier, J. et al. Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q. Sci. Transl Med. 14, eabi8593 (2022).

    Article  CAS  Google Scholar 

  173. Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016).

    Article  CAS  Google Scholar 

  174. Bie, B., Wu, J., Foss, J. F. & Naguib, M. Activation of mGluR1 mediates C1q-dependent microglial phagocytosis of glutamatergic synapses in Alzheimer’s rodent models. Mol. Neurobiol. 56, 5568–5585 (2019).

    Article  CAS  Google Scholar 

  175. Shi, Q. et al. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci. Transl Med. 9, eaaf6295 (2017).

    Article  Google Scholar 

  176. Brelstaff, J., Tolkovsky, A. M., Ghetti, B., Goedert, M. & Spillantini, M. G. Living neurons with tau filaments aberrantly expose phosphatidylserine and are phagocytosed by microglia. Cell Rep. 24, 1939–1948 (2018).

    Article  CAS  Google Scholar 

  177. Dejanovic, B. et al. Changes in the synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies. Neuron 100, 1322–1336 (2018).

    Article  CAS  Google Scholar 

  178. Benetatos, J. et al. PTEN activation contributes to neuronal and synaptic engulfment by microglia in tauopathy. Acta Neuropathol. 140, 7–24 (2020).

    Article  CAS  Google Scholar 

  179. Olmos-Alonso, A. et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain 139, 891–907 (2016).

    Article  Google Scholar 

  180. Spangenberg, E. E. et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology. Brain 139, 1265–1281 (2016).

    Article  Google Scholar 

  181. Mancuso, R. et al. CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain 142, 3243–3264 (2019).

    Article  Google Scholar 

  182. Oberheim, N. A., Wang, X., Goldman, S. & Nedergaard, M. Astrocytic complexity distinguishes the human brain. Trends Neurosci. 29, 547–553 (2006).

    Article  CAS  Google Scholar 

  183. Wang, W.-Y., Tan, M.-S., Yu, J.-T. & Tan, L. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann. Transl Med. 3, 136 (2015).

    Google Scholar 

  184. Combs, C. K., Karlo, J. C., Kao, S. C. & Landreth, G. E. β-Amyloid stimulation of microglia and monocytes results in TNFα-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J. Neurosci. 21, 1179–1188 (2001).

    Article  CAS  Google Scholar 

  185. Azevedo, E. P. et al. Activated microglia mediate synapse loss and short-term memory deficits in a mouse model of transthyretin-related oculoleptomeningeal amyloidosis. Cell Death Dis. 4, e789 (2013).

    Article  CAS  Google Scholar 

  186. Sheppard, O., Coleman, M. P. & Durrant, C. S. Lipopolysaccharide-induced neuroinflammation induces presynaptic disruption through a direct action on brain tissue involving microglia-derived interleukin 1 beta. J. Neuroinflamm. 16, 106 (2019).

    Article  Google Scholar 

  187. Zhu, Y. et al. APOE genotype alters glial activation and loss of synaptic markers in mice. Glia 60, 559–569 (2012).

    Article  Google Scholar 

  188. El Hajj, H. et al. Ultrastructural evidence of microglial heterogeneity in Alzheimer’s disease amyloid pathology. J. Neuroinflamm. 16, 87 (2019).

    Article  Google Scholar 

  189. Gomez-Arboledas, A. et al. Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer’s disease. Glia 66, 637–653 (2018).

    Article  Google Scholar 

  190. Sanchez-Mico, M. V. et al. Amyloid-β impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer’s disease. Glia 69, 997–1011 (2021).

    Article  CAS  Google Scholar 

  191. Franco-Bocanegra, D. K. et al. Microglial morphology in Alzheimer’s disease and after Aβ immunotherapy. Sci. Rep. 11, 15955 (2021).

    Article  CAS  Google Scholar 

  192. Hannestad, J. et al. Safety and tolerability of GRF6019 infusions in severe Alzheimer’s disease: a phase II double-blind placebo-controlled trial. J. Alzheimers Dis. 81, 1649–1662 (2021).

    Article  CAS  Google Scholar 

  193. Izzo, N. J. et al. Preclinical and clinical biomarker studies of CT1812: a novel approach to Alzheimer’s disease modification. Alzheimers Dement. 17, 1365–1382 (2021).

    Article  CAS  Google Scholar 

  194. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03817684 (2019).

  195. Farlow, M. R. et al. A randomized, double-blind, placebo-controlled, phase II study assessing safety, tolerability, and efficacy of bryostatin in the treatment of moderately severe to severe Alzheimer’s disease. J. Alzheimers Dis. 67, 555–570 (2019).

    Article  CAS  Google Scholar 

  196. Ismail, R. et al. The effect of 40-Hz light therapy on amyloid load in patients with prodromal and clinical Alzheimer’s disease. Int. J. Alzheimers Dis. 2018, 6852303 (2018).

    Google Scholar 

  197. Pleen, J. & Townley, R. Alzheimer’s disease clinical trial update 2019–2021. J. Neurol. 269, 1038–1051 (2022).

    Article  Google Scholar 

  198. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04805983 (2022).

  199. Lansita, J. A. et al. Nonclinical development of ANX005: a humanized anti-C1q antibody for treatment of autoimmune and neurodegenerative diseases. Int. J. Toxicol. 36, 449–462 (2017).

    Article  CAS  Google Scholar 

  200. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04701164 (2021).

  201. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04514367 (2022).

  202. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04121208 (2020).

  203. Cannarile, M. A. et al. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J. Immunother. Cancer 5, 53 (2017).

    Article  Google Scholar 

  204. Livingston, G. et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 396, 413–446 (2020).

    Article  Google Scholar 

  205. Casaletto, K. B. et al. Microglial correlates of late life physical activity: relationship with synaptic and cognitive aging in older adults. J. Neurosci. 42, 288–298 (2022).

    Article  CAS  Google Scholar 

  206. Spires-Jones, T. L. & Ritchie, C. W. A brain boost to fight Alzheimer’s disease. Science 361, 975–976 (2018).

    Article  CAS  Google Scholar 

  207. Choi, S. H. et al. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science 361, eaan8821 (2018).

    Article  Google Scholar 

  208. Yiannopoulou, K. G., Anastasiou, A. I., Zachariou, V. & Pelidou, S.-H. Reasons for failed trials of disease-modifying treatments for Alzheimer disease and their contribution in recent research. Biomedicines 7, E97 (2019).

    Article  Google Scholar 

  209. Colom-Cadena, M. et al. The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease. Alzheimers Res. Ther. 12, 21 (2020).

    Article  Google Scholar 

  210. Utz, J. et al. Cerebrospinal fluid of patients with Alzheimer’s disease contains increased percentages of synaptophysin-bearing microvesicles. Front. Aging Neurosci. 13, 683115 (2021).

    Article  Google Scholar 

  211. Xiao, M.-F. et al. NPTX2 and cognitive dysfunction in Alzheimer’s disease. Elife 6, e23798 (2017).

    Article  Google Scholar 

  212. Brinkmalm, G. et al. A parallel reaction monitoring mass spectrometric method for analysis of potential CSF biomarkers for Alzheimer’s disease. Proteom. Clin. Appl. 12, 1700131 (2018).

    Article  Google Scholar 

  213. Kvartsberg, H. et al. The intact postsynaptic protein neurogranin is reduced in brain tissue from patients with familial and sporadic Alzheimer’s disease. Acta Neuropathol. 137, 89–102 (2019).

    Article  Google Scholar 

  214. Portelius, E. et al. Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer’s disease. Brain 138, 3373–3385 (2015).

    Article  Google Scholar 

  215. Tarawneh, R. et al. Diagnostic and prognostic utility of the synaptic marker neurogranin in Alzheimer disease. JAMA Neurol. 73, 561–571 (2016).

    Article  Google Scholar 

  216. Lleó, A. et al. Changes in synaptic proteins precede neurodegeneration markers in preclinical Alzheimer’s disease cerebrospinal fluid. Mol. Cell Proteom. 18, 546–560 (2019).

    Article  Google Scholar 

  217. Suárez-Calvet, M. et al. sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer’s disease and associate with neuronal injury markers. EMBO Mol. Med. 8, 466–476 (2016).

    Article  Google Scholar 

  218. Piccio, L. et al. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 131, 925–933 (2016).

    Article  CAS  Google Scholar 

  219. Heslegrave, A. et al. Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer’s disease. Mol. Neurodegener. 11, 3 (2016).

    Article  Google Scholar 

  220. Fukuyama, R., Izumoto, T. & Fushiki, S. The cerebrospinal fluid level of glial fibrillary acidic protein is increased in cerebrospinal fluid from Alzheimer’s disease patients and correlates with severity of dementia. Eur. Neurol. 46, 35–38 (2001).

    Article  CAS  Google Scholar 

  221. Benedet, A. L. et al. Differences between plasma and cerebrospinal fluid glial fibrillary acidic protein levels across the Alzheimer disease continuum. JAMA Neurol. 78, 1471–1483 (2021).

    Article  Google Scholar 

  222. Teitsdottir, U. D. et al. Association of glial and neuronal degeneration markers with Alzheimer’s disease cerebrospinal fluid profile and cognitive functions. Alzheimers Res. Ther. 12, 92 (2020).

    Article  CAS  Google Scholar 

  223. Olsson, B. et al. Microglial markers are elevated in the prodromal phase of Alzheimer’s disease and vascular dementia. J. Alzheimers Dis. 33, 45–53 (2013).

    Article  CAS  Google Scholar 

  224. Craig-Schapiro, R. et al. YKL-40: a novel prognostic fluid biomarker for preclinical Alzheimer’s disease. Biol. Psychiatry 68, 903–912 (2010).

    Article  CAS  Google Scholar 

  225. Corrêa, J. D., Starling, D., Teixeira, A. L., Caramelli, P. & Silva, T. A. Chemokines in CSF of Alzheimer’s disease patients. Arq. Neuropsiquiatr. 69, 455–459 (2011).

    Article  Google Scholar 

  226. Mattsson, N. et al. Cerebrospinal fluid microglial markers in Alzheimer’s disease: elevated chitotriosidase activity but lack of diagnostic utility. Neuromol. Med. 13, 151–159 (2011).

    Article  CAS  Google Scholar 

  227. Watabe-Rudolph, M. et al. Chitinase enzyme activity in CSF is a powerful biomarker of Alzheimer disease. Neurology 78, 569–577 (2012).

    Article  CAS  Google Scholar 

  228. Humpel, C. & Hochstrasser, T. Cerebrospinal fluid and blood biomarkers in Alzheimer’s disease. World J. Psychiatry 1, 8–18 (2011).

    Article  Google Scholar 

  229. Palmqvist, S. et al. Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer’s disease. EMBO Mol. Med. 11, e11170 (2019).

    Article  CAS  Google Scholar 

  230. Stevenson, A. J. et al. Characterisation of an inflammation-related epigenetic score and its association with cognitive ability. Clin. Epigenetics 12, 113 (2020).

    Article  CAS  Google Scholar 

  231. Finnema, S. J. et al. Imaging synaptic density in the living human brain. Sci. Transl Med. 8, 348ra96 (2016).

    Article  Google Scholar 

  232. Mecca, A. P. et al. In vivo measurement of widespread synaptic loss in Alzheimer’s disease with SV2A PET. Alzheimers Dement. 16, 974–982 (2020).

    Article  Google Scholar 

  233. Chen, M.-K. et al. Assessing synaptic density in Alzheimer disease with synaptic vesicle glycoprotein 2A positron emission tomographic imaging. JAMA Neurol. 75, 1215–1224 (2018).

    Article  Google Scholar 

  234. Mecca, A. P. et al. Association of entorhinal cortical tau deposition and hippocampal synaptic density in older individuals with normal cognition and early Alzheimer’s disease. Neurobiol. Aging 111, 44–53 (2022).

    Article  Google Scholar 

  235. Scheff, S. W., Price, D. A., Schmitt, F. A., DeKosky, S. T. & Mufson, E. J. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68, 1501–1508 (2007).

    Article  CAS  Google Scholar 

  236. Beach, T. G., Walker, R. & McGeer, E. G. Patterns of gliosis in Alzheimer’s disease and aging cerebrum. Glia 2, 420–436 (1989).

    Article  CAS  Google Scholar 

  237. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02386306 (2016).

  238. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04015076 (2020).

  239. Hu, W. et al. Development of a novel therapeutic suppressor of brain proinflammatory cytokine up-regulation that attenuates synaptic dysfunction and behavioral deficits. Bioorg. Med. Chem. Lett. 17, 414–418 (2007).

    Article  CAS  Google Scholar 

  240. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04120233 (2021).

  241. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04008355 (2022).

  242. Decourt, B. et al. MCLENA-1: a phase II clinical trial for the assessment of safety, tolerability, and efficacy of lenalidomide in patients with mild cognitive impairment due to Alzheimer’s disease. Open. Access. J. Clin. Trials 12, 1–13 (2020).

    Article  Google Scholar 

  243. Marschallinger, J. et al. Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug. Nat. Commun. 6, 8466 (2015).

    Article  CAS  Google Scholar 

  244. Xiong, L. Y. et al. Leukotriene receptor antagonist use and cognitive decline in normal cognition, mild cognitive impairment, and Alzheimer’s dementia. Alzheimers Res. Ther. 13, 147 (2021).

    Article  CAS  Google Scholar 

  245. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03991988 (2021).

  246. Munoz, L. et al. A novel p38α MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer’s disease mouse model. J. Neuroinflamm. 4, 21 (2007).

    Article  Google Scholar 

  247. Scheltens, P. et al. An exploratory clinical study of p38α kinase inhibition in Alzheimer’s disease. Ann. Clin. Transl Neurol. 5, 464–473 (2018).

    Article  CAS  Google Scholar 

  248. Prins, N. D. et al. A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer’s disease. Alzheimers Res. Ther. 13, 106 (2021).

    Article  CAS  Google Scholar 

  249. Ricciarelli, R. & Fedele, E. Phosphodiesterase 4D: an enzyme to remember. Br. J. Pharmacol. 172, 4785–4789 (2015).

    Article  CAS  Google Scholar 

  250. Cui, S.-Y. et al. Protection from amyloid β peptide-induced memory, biochemical, and morphological deficits by a phosphodiesterase-4D allosteric inhibitor. J. Pharmacol. Exp. Ther. 371, 250–259 (2019).

    Article  CAS  Google Scholar 

  251. Brazier, D., Perry, R., Keane, J., Barrett, K. & Elmaleh, D. R. Pharmacokinetics of cromolyn and ibuprofen in healthy elderly volunteers. Clin. Drug Investig. 37, 1025–1034 (2017).

    Article  CAS  Google Scholar 

  252. Xiao, S. et al. A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer’s dementia. Alzheimers Res. Ther. 13, 62 (2021).

    Article  CAS  Google Scholar 

  253. Wang, T. et al. A phase II randomized trial of sodium oligomannate in Alzheimer’s dementia. Alzheimers Res. Ther. 12, 110 (2020).

    Article  CAS  Google Scholar 

  254. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02097056 (2016).

  255. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01054976 (2012).

  256. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00622713 (2011).

  257. Davis, K. L. et al. A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer’s disease. N. Engl. J. Med. 327, 1253–1259 (1992).

    Article  CAS  Google Scholar 

  258. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00469456 (2009).

  259. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02750306 (2019).

  260. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03822208 (2021).

  261. Tao, C.-C. et al. Galectin-3 promotes Aβ oligomerization and Aβ toxicity in a mouse model of Alzheimer’s disease. Cell Death Differ. 27, 192–209 (2020).

    Article  CAS  Google Scholar 

  262. Boza-Serrano, A. et al. Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease. Acta Neuropathol. 138, 251–273 (2019).

    Article  CAS  Google Scholar 

  263. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05074498 (2022).

  264. Smith, E. S. et al. SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. Neurobiol. Dis. 73, 254–268 (2015).

    Article  CAS  Google Scholar 

  265. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04381468 (2022).

  266. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04592874 (2022).

  267. Butchart, J. et al. Etanercept in Alzheimer disease: a randomized, placebo-controlled, double-blind, phase 2 trial. Neurology 84, 2161–2168 (2015).

    Article  CAS  Google Scholar 

  268. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00818662 (2021).

  269. Macpherson, L. J. et al. Dynamic labelling of neural connections in multiple colours by trans-synaptic fluorescence complementation. Nat. Commun. 6, 10024 (2015).

    Article  CAS  Google Scholar 

  270. Sama, D. M. et al. Inhibition of soluble tumor necrosis factor ameliorates synaptic alterations and Ca2+ dysregulation in aged rats. PLoS ONE 7, e38170 (2012).

    Article  CAS  Google Scholar 

  271. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03943264 (2022).

  272. Kiyota, T. et al. Granulocyte-macrophage colony-stimulating factor neuroprotective activities in Alzheimer’s disease mice. J. Neuroimmunol. 319, 80–92 (2018).

    Article  CAS  Google Scholar 

  273. US National Library of Medicine ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04902703 (2022).

  274. Hongpaisan, J., Sun, M.-K. & Alkon, D. L. PKC ε activation prevents synaptic loss, Aβ elevation, and cognitive deficits in Alzheimer’s disease transgenic mice. J. Neurosci. 31, 630–643 (2011).

    Article  CAS  Google Scholar 

  275. McClean, P. L., Parthsarathy, V., Faivre, E. & Hölscher, C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J. Neurosci. 31, 6587–6594 (2011).

    Article  CAS  Google Scholar 

  276. Robbins, M., Clayton, E. & Kaminski Schierle, G. S. Synaptic tau: a pathological or physiological phenomenon? Acta Neuropathol. Commun. 9, 149 (2021).

    Article  CAS  Google Scholar 

  277. Carlyle, B. C. et al. cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex. Proc. Natl Acad. Sci. USA 111, 5036–5041 (2014).

    Article  CAS  Google Scholar 

  278. Li, C. & Götz, J. Somatodendritic accumulation of Tau in Alzheimer’s disease is promoted by Fyn‐mediated local protein translation. EMBO J. 36, 3120–3138 (2017).

    Article  CAS  Google Scholar 

  279. Alonso, A. et al. Hyperphosphorylation induces self-assembly of τ into tangles of paired helical filaments/straight filaments. Proc. Natl Acad. Sci. USA 98, 6923–6928 (2001).

    Article  CAS  Google Scholar 

  280. Ballatore, C., Lee, V. M.-Y. & Trojanowski, J. Q. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat. Rev. Neurosci. 8, 663–672 (2007).

    Article  CAS  Google Scholar 

  281. Rocher, A. B. et al. Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs. Exp. Neurol. 223, 385–393 (2010).

    Article  CAS  Google Scholar 

  282. Crimins, J. L., Rocher, A. B. & Luebke, J. I. Electrophysiological changes precede morphological changes to frontal cortical pyramidal neurons in the rTg4510 mouse model of progressive tauopathy. Acta Neuropathol. 124, 777–795 (2012).

    Article  CAS  Google Scholar 

  283. Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351 (2007).

    Article  CAS  Google Scholar 

  284. Ghag, G. et al. Soluble tau aggregates, not large fibrils, are the toxic species that display seeding and cross‐seeding behavior. Protein Sci. 27, 1901–1909 (2018).

    Article  CAS  Google Scholar 

  285. Jiang, L., Zhao, J., Cheng, J.-X. & Wolozin, B. Tau oligomers and fibrils exhibit differential patterns of seeding and association with RNA binding proteins. Front. Neurol. 11, 579434 (2020).

    Article  Google Scholar 

  286. Menkes-Caspi, N. et al. Pathological tau disrupts ongoing network activity. Neuron 85, 959–966 (2015).

    Article  CAS  Google Scholar 

  287. Meyer-Luehmann, M. et al. Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host. Science 313, 1781–1784 (2006).

    Article  CAS  Google Scholar 

  288. Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909–913 (2009).

    Article  CAS  Google Scholar 

  289. Falcon, B. et al. Conformation determines the seeding potencies of native and recombinant tau aggregates. J. Biol. Chem. 290, 1049–1065 (2015).

    Article  CAS  Google Scholar 

  290. Furman, J. L. et al. Widespread tau seeding activity at early Braak stages. Acta Neuropathol. 133, 91–100 (2017).

    Article  CAS  Google Scholar 

  291. Mirbaha, H., Holmes, B. B., Sanders, D. W., Bieschke, J. & Diamond, M. I. Tau trimers are the minimal propagation unit spontaneously internalized to seed intracellular aggregation. J. Biol. Chem. 290, 14893–14903 (2015).

    Article  CAS  Google Scholar 

  292. DeVos, S. L. et al. Synaptic tau seeding precedes tau pathology in human Alzheimer’s disease brain. Front. Neurosci. 12, 267 (2018).

    Article  Google Scholar 

  293. d’Errico, P. et al. Microglia contribute to the propagation of Aβ into unaffected brain tissue. Nat. Neurosci. 25, 20–25 (2022).

    Article  Google Scholar 

  294. Hopp, S. C. et al. The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease. J. Neuroinflamm. 15, 269 (2018).

    Article  Google Scholar 

  295. Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015).

    Article  CAS  Google Scholar 

  296. Clayton, K. et al. Plaque associated microglia hyper-secrete extracellular vesicles and accelerate tau propagation in a humanized APP mouse model. Mol. Neurodegener. 16, 18 (2021).

    Article  CAS  Google Scholar 

  297. Busche, M. A. & Hyman, B. T. Synergy between amyloid-β and tau in Alzheimer’s disease. Nat. Neurosci. 23, 1183–1193 (2020).

    Article  CAS  Google Scholar 

  298. Pooler, A. M. et al. Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer’s disease. Acta Neuropathol. Commun. 3, 14 (2015).

    Article  Google Scholar 

  299. Adams, J. N., Maass, A., Harrison, T. M., Baker, S. L. & Jagust, W. J. Cortical tau deposition follows patterns of entorhinal functional connectivity in aging. eLife 8, e49132 (2019).

    Article  CAS  Google Scholar 

  300. Wan, Y.-W. et al. Meta-analysis of the Alzheimer’s disease human brain transcriptome and functional dissection in mouse models. Cell Rep. 32, 107908 (2020).

    Article  CAS  Google Scholar 

  301. Chen, W.-T. et al. Spatial transcriptomics and in situ sequencing to study Alzheimer’s disease. Cell 182, 976–991 (2020).

    Article  CAS  Google Scholar 

  302. Zhou, Y. et al. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat. Med. 26, 131–142 (2020).

    Article  CAS  Google Scholar 

  303. Mehta, D., Jackson, R., Paul, G., Shi, J. & Sabbagh, M. Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010–2015. Expert. Opin. Investig. Drugs 26, 735–739 (2017).

    Article  CAS  Google Scholar 

  304. Makin, S. The amyloid hypothesis on trial. Nature 559, S4–S7 (2018).

    Article  CAS  Google Scholar 

  305. Lazic, S. E. The problem of pseudoreplication in neuroscientific studies: is it affecting your analysis? BMC Neurosci. 11, 5 (2010).

    Article  Google Scholar 

  306. Brown, A. W., Kaiser, K. A. & Allison, D. B. Issues with data and analyses: errors, underlying themes, and potential solutions. Proc. Natl Acad. Sci. USA 115, 2563–2570 (2018).

    Article  CAS  Google Scholar 

  307. du Sert, N. P. et al. Reporting animal research: explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol. 18, e3000411 (2020).

    Article  Google Scholar 

  308. Deaton, A. & Cartwright, N. Understanding and misunderstanding randomized controlled trials. Soc. Sci. Med. 210, 2–21 (2018).

    Article  Google Scholar 

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Glossary

APP/PS1 transgenic mice

Mice that express the human amyloid precursor protein (APP) gene with the Swedish mutation and presenilin gene with exon 9 deletion; both are genetic causes of early-onset AD.

BV2 microglia

A mouse immortalized cell line developed to model microglia in vitro.

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Tzioras, M., McGeachan, R.I., Durrant, C.S. et al. Synaptic degeneration in Alzheimer disease. Nat Rev Neurol 19, 19–38 (2023). https://doi.org/10.1038/s41582-022-00749-z

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