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Res."],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Alzheimer\u2019s disease (AD) is a predominant form of dementia in elderly. In sporadic AD and in families with higher risk of AD, correlation with apolipoprotein E4\n                    <jats:italic>(APOE)<\/jats:italic>\n                    allele expression has been found. How\n                    <jats:italic>APOE4<\/jats:italic>\n                    induces its pathological effects is still unclear. Several studies indicate that autophagy, a major degradation pathway trough the lysosome, may be compromised in AD. Here we studied, the effects of\n                    <jats:italic>APOE<\/jats:italic>\n                    isoforms expression in microglia cells. By using an in-situ model, the clearance of A\u03b2 plaques from brain sections of transgenic 5xFAD mice by the\n                    <jats:italic>APOE<\/jats:italic>\n                    expressing microglia was examined. The results show that APOE4 microglia has Impairment In clearance of insoluble A\u03b2 plaques as compared to\n                    <jats:italic>APOE3<\/jats:italic>\n                    and\n                    <jats:italic>APOE2<\/jats:italic>\n                    microglia. Furthermore, APOE4 affect the uptake of soluble A\u03b2. We found that microglia expressing\n                    <jats:italic>APOE4<\/jats:italic>\n                    exhibit reduced autophagic flux as compared to those expressing\n                    <jats:italic>APOE3<\/jats:italic>\n                    . The autophagy inhibitor chloroquine also blocked A\u03b2 plaque uptake in APOE3 expressing cells. Furthermore, we found that\n                    <jats:italic>APOE4<\/jats:italic>\n                    expressing microglia have altered mitochondrial dynamics protein expression, mitochondrial morphology and mitochondrial activity compared to those expressing\n                    <jats:italic>APOE2<\/jats:italic>\n                    , and\n                    <jats:italic>APOE3<\/jats:italic>\n                    . Rapamycin treatment corrected Mitochondrial Membrane Potential in\n                    <jats:italic>APOE4-<\/jats:italic>\n                    expressing cells. Taken together, these findings suggest that\n                    <jats:italic>APOE4<\/jats:italic>\n                    impairs the activation of autophagy, mitophagy, and A\u03b2 clearance and that autophagy-inducing treatments, such as rapamycin, can enhance autophagy and mitochondrial functions in\n                    <jats:italic>APOE4<\/jats:italic>\n                    expressing microglia. Our results reveal a direct link between\n                    <jats:italic>APOE4<\/jats:italic>\n                    to autophagy activity in microglia, suggesting that the pathological effects of\n                    <jats:italic>APOE4<\/jats:italic>\n                    could be counteracted by pharmacological treatments inducing autophagy, such as rapamycin.\n                  <\/jats:p>","DOI":"10.1007\/s00011-025-02016-5","type":"journal-article","created":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T08:18:54Z","timestamp":1743668334000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["APOE4 impairs autophagy and A\u03b2 clearance by microglial cells"],"prefix":"10.1007","volume":"74","author":[{"given":"Rawan","family":"Bassal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Rivkin-Natan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alon","family":"Rabinovich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Moris","family":"Michaelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Frenkel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronit","family":"Pinkas-Kramarski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,1]]},"reference":[{"key":"2016_CR1","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1002\/ca.980080612","volume":"8","author":"A Alzheimer","year":"1995","unstructured":"Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR. 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