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It is posited that C1 binding initiates complement activation on synapses; C3 fragments then tag them for microglial phagocytosis. However, the precise mechanisms of complement-mediated synaptic loss remain unclear, and the role of the lytic membrane attack complex (MAC) is unexplored. We here address several knowledge gaps: (i) is complement activated through to MAC at the synapse? (ii) does MAC contribute to synaptic loss? (iii) can MAC inhibition prevent synaptic loss? Novel methods were developed and optimised to quantify C1q, C3 fragments and MAC in total and regional brain homogenates and synaptoneurosomes from WT and\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>NL\u2212G\u2212F<\/jats:italic>\n                    <\/jats:sup>\n                    Alzheimer\u2019s disease model mouse brains at 3, 6, 9 and 12\u00a0months of age. The impact on synapse loss of systemic treatment with a MAC blocking antibody and gene knockout of a MAC component was assessed in Alzheimer\u2019s disease model mice. A significant increase in C1q, C3 fragments and MAC was observed in\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>NL\u2212G\u2212F<\/jats:italic>\n                    <\/jats:sup>\n                    mice compared to controls, increasing with age and severity. Administration of anti-C7 antibody to\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>NL\u2212G\u2212F<\/jats:italic>\n                    <\/jats:sup>\n                    mice modulated synapse loss, reflected by the density of dendritic spines in the vicinity of plaques. Constitutive knockout of C6 significantly reduced synapse loss in 3xTg-AD mice. We demonstrate that complement dysregulation occurs in Alzheimer\u2019s disease mice involving the activation (C1q; C3b\/iC3b) and terminal (MAC) pathways in brain areas associated with pathology. Inhibition or ablation of MAC formation reduced synapse loss in two Alzheimer\u2019s disease mouse models, demonstrating that MAC formation is a driver of synapse loss. We suggest that MAC directly damages synapses, analogous to neuromuscular junction destruction in myasthenia gravis.\n                  <\/jats:p>","DOI":"10.1186\/s40478-022-01404-w","type":"journal-article","created":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T06:02:41Z","timestamp":1657087361000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":90,"title":["Terminal complement pathway activation drives synaptic loss in Alzheimer\u2019s disease models"],"prefix":"10.1186","volume":"10","author":[{"given":"Sarah M.","family":"Carpanini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Torvell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan J.","family":"Bevan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A. 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