AUTHOR=Oblak Adrian L. , Kotredes Kevin P. , Pandey Ravi S. , Reagan Alaina M. , Ingraham Cynthia , Perkins Bridget , Lloyd Christopher , Baker Deborah , Lin Peter B. , Soni Disha M. , Tsai Andy P. , Persohn Scott A. , Bedwell Amanda A. , Eldridge Kierra , Speedy Rachael , Meyer Jill A. , Peters Johnathan S. , Figueiredo Lucas L. , Sasner Michael , Territo Paul R. , Sukoff Rizzo Stacey J. , Carter Gregory W. , Lamb Bruce T. , Howell Gareth R. 

TITLE=Plcg2M28L Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer’s Disease-Relevant Phenotypes in Mice

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=14

YEAR=2022

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2022.886575

DOI=10.3389/fnagi.2022.886575

ISSN=1663-4365

ABSTRACT=<p>Obesity is recognized as a significant risk factor for Alzheimer’s 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 <italic>APOE4</italic> and a variant in triggering receptor expressed on myeloid cells 2 (<italic>Trem2<sup>R47H</sup></italic>). We have termed this model, LOAD1. Additional variants including the M28L variant in phospholipase C Gamma 2 (<italic>Plcg2<sup>M28L</sup></italic>) and the 677C &gt; T variant in methylenetetrahydrofolate reductase (<italic>Mthfr</italic><sup>677C &gt;</sup><italic><sup>T</sup></italic>) were engineered by CRISPR onto LOAD1 to generate LOAD1.<italic>Plcg2<sup>M28L</sup></italic> and LOAD1.<italic>Mthfr</italic><sup>677C &gt;</sup><italic><sup>T</sup></italic>. 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.<italic>Plcg2<sup>M28L</sup></italic> 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.<italic>Mthfr</italic><sup>677C &gt;</sup><italic><sup>T</sup></italic> animals fed with HFD. Furthermore, LOAD1.<italic>Plcg2<sup>M28L</sup></italic> but not LOAD1.<italic>Mthfr</italic><sup>677C &gt;</sup><italic><sup>T</sup></italic> 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.</p>