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In AD, a subpopulation of astrocytes acquires a neurotoxic phenotype which prompts them to lose typical physiological features. While the underlying molecular mechanisms are still unknown, evidence suggests that myeloid differentiation primary response 88 (MyD88) adaptor protein may play a role in coordinating these cells' immune responses in AD. Herein, we combined studies in human postmortem samples with a conditional genetic knockout mouse model to investigate the link between MyD88 and astrocytes in AD. In silico analyses of bulk and cell\u2010specific transcriptomic data from human postmortem brains demonstrated an upregulation of MyD88 expression in astrocytes in AD versus non\u2010AD individuals. Proteomic studies revealed an increase in glial fibrillary acidic protein in multiple brain regions of AD subjects. These studies also showed that although overall MyD88 steady\u2010state levels were unaffected by AD, this protein was enriched in astrocytes near amyloid plaques and neurofibrillary tangles. Functional studies in mice indicated that the deletion of astrocytic MyD88 protected animals from the acute synaptic toxicity and cognitive impairment caused by the intracerebroventricular administration of \u03b2\u2010amyloid (A\u03b2). Lastly, unbiased proteomic analysis revealed that loss of astrocytic MyD88 resulted in altered astrocyte reactivity, lower levels of immune\u2010related proteins, and higher expression of synaptic\u2010related proteins in response to A\u03b2. Our studies provide evidence of the pivotal role played by MyD88 in the regulation of astrocytes response to AD.<\/jats:p>","DOI":"10.1002\/glia.24285","type":"journal-article","created":{"date-parts":[[2022,10,22]],"date-time":"2022-10-22T07:29:50Z","timestamp":1666423790000},"page":"431-449","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Deletion of <scp>MyD88<\/scp> in astrocytes prevents \u03b2\u2010amyloid\u2010induced neuropathology in mice"],"prefix":"10.1002","volume":"71","author":[{"given":"Tee","family":"Jong Huat","sequence":"first","affiliation":[{"name":"Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute The University of Queensland  Brisbane Queensland Australia"},{"name":"Centre for Stem Cell Ageing and Regenerative Engineering The University of Queensland  Brisbane Queensland 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Memory Impairments and Neurological Disorders University of California, Irvine  Irvine California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley N.","family":"Sue","sequence":"additional","affiliation":[{"name":"Institute for Memory Impairments and Neurological Disorders University of California, Irvine  Irvine California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mehdi","family":"Mirzaei","sequence":"additional","affiliation":[{"name":"Macquarie Medical School, Faculty of Medicine, Health and Human Sciences Macquarie University  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank M.","family":"LaFerla","sequence":"additional","affiliation":[{"name":"Institute for Memory Impairments and Neurological Disorders University of California, Irvine  Irvine California USA"},{"name":"Department of Neurobiology and Behavior University of California, Irvine  Irvine California 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