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

Frontiers in Aging Neuroscience

Gareth R. Howell¹  Adrian L. Oblak¹  Gregory W. Carter²  Stacey J. Sukoff Rizzo³  Bruce T. Lamb⁴  Andy P. Tsai⁵  Christopher Lloyd⁵  Amanda A. Bedwell⁵  Lucas L. Figueiredo⁵  Deborah Baker⁵  Disha M. Soni⁵  Johnathan S. Peters⁵  Kierra Eldridge⁵  Bridget Perkins⁵  Scott A. Persohn⁵  Jill A. Meyer⁵  Peter B. Lin⁵  Cynthia Ingraham⁵  Rachael Speedy⁵  Alaina M. Reagan⁶  Kevin P. Kotredes⁷  Michael Sasner⁷  Paul R. Territo⁷  Ravi S. Pandey⁸ 

[1] Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, United States;Department of Medicine, Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States;Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, United States;;Department of Radiology &Indiana University School of Medicine, Indianapolis, IN, United States;Jackson Laboratory for Genomic Medicine, Farmington, CT, United States;Stark Neurosciences Research Institute, Indianapolis, IN, United States;The Jackson Laboratory, Bar Harbor, ME, United States;

关键词: Alzheime’s disease;    transcriptomics;    diet;    obesity;    genetic risk alleles;    predisposition;   

DOI  :  10.3389/fnagi.2022.886575

来源: DOAJ

【 摘 要 】

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 APOE4 and a variant in triggering receptor expressed on myeloid cells 2 (Trem2R47H). We have termed this model, LOAD1. Additional variants including the M28L variant in phospholipase C Gamma 2 (Plcg2M28L) and the 677C > T variant in methylenetetrahydrofolate reductase (Mthfr677C >T) were engineered by CRISPR onto LOAD1 to generate LOAD1.Plcg2M28L and LOAD1.Mthfr677C >T. 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.Plcg2M28L 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.Mthfr677C >T animals fed with HFD. Furthermore, LOAD1.Plcg2M28L but not LOAD1.Mthfr677C >T 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.

【 授权许可】

Unknown