{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T01:00:59Z","timestamp":1791594059138,"version":"4.3.4"},"reference-count":76,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T00:00:00Z","timestamp":1656028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54AG054345"],"award-info":[{"award-number":["U54AG054345"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K01AG054753"],"award-info":[{"award-number":["K01AG054753"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>\n                    Obesity is recognized as a significant risk factor for Alzheimer\u2019s disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority of studies, to date, have focused on the use of early-onset AD models. Here, we evaluate the impact of genetic risk factors on late-onset AD (LOAD) in mice fed with a high fat\/high sugar diet (HFD). We focused on three mouse models created through the IU\/JAX\/PITT MODEL-AD Center. These included a combined risk model with\n                    <jats:italic>APOE4<\/jats:italic>\n                    and a variant in triggering receptor expressed on myeloid cells 2 (\n                    <jats:italic>\n                      Trem2\n                      <jats:sup>R47H<\/jats:sup>\n                    <\/jats:italic>\n                    ). We have termed this model, LOAD1. Additional variants including the M28L variant in phospholipase C Gamma 2 (\n                    <jats:italic>\n                      Plcg2\n                      <jats:sup>M28L<\/jats:sup>\n                    <\/jats:italic>\n                    ) and the 677C &amp;gt; T variant in methylenetetrahydrofolate reductase (\n                    <jats:italic>Mthfr<\/jats:italic>\n                    <jats:sup>677C &amp;gt;<\/jats:sup>\n                    <jats:italic>\n                      <jats:sup>T<\/jats:sup>\n                    <\/jats:italic>\n                    ) were engineered by CRISPR onto LOAD1 to generate LOAD1.\n                    <jats:italic>\n                      Plcg2\n                      <jats:sup>M28L<\/jats:sup>\n                    <\/jats:italic>\n                    and LOAD1.\n                    <jats:italic>Mthfr<\/jats:italic>\n                    <jats:sup>677C &amp;gt;<\/jats:sup>\n                    <jats:italic>\n                      <jats:sup>T<\/jats:sup>\n                    <\/jats:italic>\n                    . At 2 months of age, animals were placed on an HFD that induces obesity or a control diet (CD), until 12 months of age. Throughout the study, blood was collected to assess the levels of cholesterol and glucose. Positron emission tomography\/computed tomography (PET\/CT) was completed prior to sacrifice to image for glucose utilization and brain perfusion. After the completion of the study, blood and brains were collected for analysis. As expected, animals fed a HFD, showed a significant increase in body weight compared to those fed a CD. Glucose increased as a function of HFD in females only with cholesterol increasing in both sexes. Interestingly, LOAD1.\n                    <jats:italic>\n                      Plcg2\n                      <jats:sup>M28L<\/jats:sup>\n                    <\/jats:italic>\n                    demonstrated an increase in microglia density and alterations in regional brain glucose and perfusion on HFD. These changes were not observed in LOAD1 or LOAD1.\n                    <jats:italic>Mthfr<\/jats:italic>\n                    <jats:sup>677C &amp;gt;<\/jats:sup>\n                    <jats:italic>\n                      <jats:sup>T<\/jats:sup>\n                    <\/jats:italic>\n                    animals fed with HFD. Furthermore, LOAD1.\n                    <jats:italic>\n                      Plcg2\n                      <jats:sup>M28L<\/jats:sup>\n                    <\/jats:italic>\n                    but not LOAD1.\n                    <jats:italic>Mthfr<\/jats:italic>\n                    <jats:sup>677C &amp;gt;<\/jats:sup>\n                    <jats:italic>\n                      <jats:sup>T<\/jats:sup>\n                    <\/jats:italic>\n                    or LOAD1 animals showed transcriptomics correlations with human AD modules. Our results show that HFD affects the brain in a genotype-specific manner. Further insight into this process may have significant implications for the development of lifestyle interventions for the treatment of AD.\n                  <\/jats:p>","DOI":"10.3389\/fnagi.2022.886575","type":"journal-article","created":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T01:44:51Z","timestamp":1656035091000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":29,"title":["Plcg2M28L Interacts With High Fat\/High Sugar Diet to Accelerate Alzheimer\u2019s Disease-Relevant Phenotypes in Mice"],"prefix":"10.3389","volume":"14","author":[{"given":"Adrian L.","family":"Oblak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin P.","family":"Kotredes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi S.","family":"Pandey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaina M.","family":"Reagan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Ingraham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bridget","family":"Perkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Lloyd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter B.","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Disha M.","family":"Soni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy P.","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A.","family":"Persohn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda A.","family":"Bedwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kierra","family":"Eldridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Speedy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill A.","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnathan S.","family":"Peters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas L.","family":"Figueiredo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Sasner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R.","family":"Territo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacey J.","family":"Sukoff Rizzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory W.","family":"Carter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce T.","family":"Lamb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth R.","family":"Howell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,24]]},"reference":[{"key":"B1","author":"Agatston","year":"2003","journal-title":"The South Beach Diet : The Delicious, Doctor-Designed, Foolproof Plan For Fast And Healthy Weight Loss."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/sdata.2016.89","article-title":"Human whole genome genotype and transcriptome data for Alzheimer\u2019s and other neurodegenerative diseases.","volume":"3","author":"Allen","year":"2016","journal-title":"Sci. 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