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In AD pathology, microglial cells not only are unable to remove \u03b2-amyloid (A\u03b2) plaques and invading pathogens but also are involved in synaptic pruning, chronic neuroinflammation, and neuronal degeneration. Microglial cells possess many different inhibitory immune checkpoint receptors, such as PD-1, LILRB2-4, Siglecs, and SIRP\u03b1 receptors, which can be targeted by diverse cell membrane-bound and soluble ligand proteins to suppress the functions of microglia. Interestingly, in the brains of AD patients there are elevated levels of many of the inhibitory ligands acting via these inhibitory checkpoint receptors. For instance, A\u03b2 oligomers, ApoE4, and fibronectin are able to stimulate the LILRB2-4 receptors. Increased deposition of sialoglycans, e.g., gangliosides, inhibits microglial function via Siglec receptors. AD pathology augments the accumulation of senescent cells, which are known to possess a high level of PD-L1 proteins, and thus, they can evade immune surveillance. A decrease in the expression of SIRP\u03b1 receptor in microglia and its ligand CD47 in neurons enhances the phagocytic pruning of synapses in AD brains. Moreover, cerebral neurons contain inhibitory checkpoint receptors which can inhibit axonal growth, reduce synaptic plasticity, and impair learning and memory. It seems that inappropriate inhibitory immune checkpoint signaling impairs the functions of microglia and neurons thus promoting AD pathogenesis.<\/jats:p>\n <\/jats:sec>\n \n Key messages<\/jats:title>\n \n \n \n Microglial cells have a major role in the pathogenesis of AD.<\/jats:p>\n <\/jats:list-item>\n \n A decline in immune activity of microglia promotes AD pathology.<\/jats:p>\n <\/jats:list-item>\n \n Microglial cells and neurons contain diverse inhibitory immune checkpoint receptors.<\/jats:p>\n <\/jats:list-item>\n \n The level of ligands for inhibitory checkpoint receptors is increased in AD pathology.<\/jats:p>\n <\/jats:list-item>\n \n Impaired signaling of inhibitory immune checkpoint receptors promotes AD pathology.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1007\/s00109-024-02504-x","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T09:20:51Z","timestamp":1732699251000},"page":"1-19","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The role of inhibitory immune checkpoint receptors in the pathogenesis of Alzheimer\u2019s disease"],"prefix":"10.1007","volume":"103","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6691-6909","authenticated-orcid":false,"given":"Antero","family":"Salminen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,27]]},"reference":[{"key":"2504_CR1","doi-asserted-by":"publisher","first-page":"595","DOI":"10.15252\/emmm.201606210","volume":"8","author":"DJ Selkoe","year":"2016","unstructured":"Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer\u2019s disease at 25 years. 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