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Mol. Life Sci."],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>A rare coding variant, <jats:italic>P522R<\/jats:italic>, in the phospholipase C gamma 2 (<jats:italic>PLCG2)<\/jats:italic> gene has been identified as protective against late-onset Alzheimer\u2019s disease (AD), but the mechanism is unknown. <jats:italic>PLCG2<\/jats:italic> is exclusively expressed in microglia within the central nervous system, and altered microglial function has been implicated in the progression of AD.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Healthy control hiPSCs were CRISPR edited to generate cells heterozygous and homozygous for the PLCG2<jats:sup>P522R<\/jats:sup> variant. Microglia derived from these hiPSC\u2019s were used to investigate the impact of PLC\u03b32<jats:sup>P522R<\/jats:sup> on disease relevant processes, specifically microglial capacity to take up amyloid beta (A\u03b2) and synapses. Targeted qPCR assessment was conducted to explore expression changes in core AD linked and microglial genes, and mitochondrial function was assessed using an Agilent Seahorse assay.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Heterozygous expression of the <jats:italic>P522R<\/jats:italic> variant resulted in increased microglial clearance of A\u03b2, while preserving synapses. This was associated with the upregulation of a number of genes, including the anti-inflammatory cytokine Il-10, and the synapse-linked CX3CR1, as well as alterations in mitochondrial function, and increased cellular motility. The protective capacity of PLC\u03b32<jats:sup>P522R<\/jats:sup> appeared crucially dependent on (gene) \u2018dose\u2019, as cells homozygous for the variant showed reduced synapse preservation, and a differential gene expression profile relative to heterozygous cells.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>These findings suggest that PLC\u03b32<jats:sup>P522R<\/jats:sup> may result in increased surveillance by microglia, and prime them towards an anti-inflammatory state, with an increased capacity to respond to increasing energy demands, but highlights the delicate balance of this system, with increasing PLC\u03b32<jats:sup>P522R<\/jats:sup> \u2018dose\u2019 resulting in reduced beneficial impacts.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1007\/s00018-022-04473-1","type":"journal-article","created":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T18:15:47Z","timestamp":1659118547000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Heterozygous expression of the Alzheimer\u2019s disease-protective PLC\u03b32 P522R variant enhances A\u03b2 clearance while preserving synapses"],"prefix":"10.1007","volume":"79","author":[{"given":"Shiden","family":"Solomon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirmal Kumar","family":"Sampathkumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivo","family":"Carre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mrityunjoy","family":"Mondal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Chennell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony C.","family":"Vernon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc-David","family":"Ruepp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2677-398X","authenticated-orcid":false,"given":"Jacqueline C","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,27]]},"reference":[{"issue":"1","key":"4473_CR1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jalz.2011.10.007","volume":"8","author":"BT Hyman","year":"2012","unstructured":"Hyman BT et al (2012) National Institute on Aging-Alzheimer\u2019s Association guidelines for the neuropathologic assessment of Alzheimer\u2019s disease. 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