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We hypothesized that inhibiting the Inducible Degrader of LDLR (IDOL), an enzyme that ubiquitinates LDLR for degradation, would increase endogenous LDLR levels and attenuate amyloid pathology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      To investigate the cell\u2010type\u2013specific role of IDOL, we generated\n                      <jats:italic>Idol<\/jats:italic>\n                      conditional knockout mice on an A\u03b2\u2010amyloidosis mouse model and performed biochemical, histological, and multi\u2010omics analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      We demonstrated that neuronal, but not microglial,\n                      <jats:italic>Idol<\/jats:italic>\n                      deletion reduced amyloid accumulation and altered brain LDLR and APOE levels, indicating the critical role of neuronal IDOL\u2010LDLR in amyloid pathology. In addition, neuronal\n                      <jats:italic>Idol<\/jats:italic>\n                      deletion increased the levels of Reelin receptors important for synaptic function, and single\u2010nuclei RNA sequencing revealed significant changes associated with synaptic organization.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Neuronal IDOL, but not microglial IDOL, plays a key role in Alzheimer's disease pathogenesis by regulating the levels of brain APOE receptors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            Neuronal, but not microglial,\n                            <jats:italic>Idol<\/jats:italic>\n                            deletion reduces amyloid burden and modulates brain APOE and LDLR levels.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Deletion of neuronal\n                            <jats:italic>Idol<\/jats:italic>\n                            increases the levels of APOER2 and VLDLR, the Reelin receptors, in the brain.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Single\u2010nuclei RNA sequencing highlights the neuronal IDOL's impact on inhibitory neurons and synaptic organization.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Targeting neuronal IDOL may provide multiple therapeutic benefits in Alzheimer's disease by modulating APOE receptors.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70949","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T12:00:18Z","timestamp":1765540818000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Deletion of neuronal\n                    <i>Idol<\/i>\n                    ameliorates Alzheimer's disease\u2013related pathologies via APOE receptors"],"prefix":"10.1002","volume":"21","author":[{"given":"Hande","family":"Karahan","sequence":"first","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Department of Medical and Molecular Genetics Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Hartigan","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Medical Neuroscience Graduate Program Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Mamun","family":"Al\u2010Amin","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Department of Medical and Molecular Genetics Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sutha K.","family":"John","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Department of Medical and Molecular Genetics Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianne","family":"McCord","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Department of Medical and Molecular Genetics Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. R. Sagara","family":"Wijeratne","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Department of Biochemistry and Molecular Biology Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic J.","family":"Acri","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Medical Neuroscience Graduate Program Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C.","family":"Smith","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Medical Neuroscience Graduate Program Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke C.","family":"Dabin","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Department of Medical and Molecular Genetics Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah M. 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