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

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

doi:10.3389/fnagi.2022.886575

Plcg2^M28L Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer's Disease-Relevant Phenotypes in Mice

Front Aging Neurosci. 2022 Jun 24:14:886575. doi: 10.3389/fnagi.2022.886575. eCollection 2022.

Authors

Adrian L Oblak^{1

2

3}, Kevin P Kotredes⁴, Ravi S Pandey^{4

5}, Alaina M Reagan⁴, Cynthia Ingraham^{1

3}, Bridget Perkins^{1

3}, Christopher Lloyd^{1

3}, Deborah Baker^{1

3}, Peter B Lin^{1

3}, Disha M Soni^{1

3}, Andy P Tsai^{1

3}, Scott A Persohn^{1

3}, Amanda A Bedwell^{1

3}, Kierra Eldridge^{1

3}, Rachael Speedy^{1

3}, Jill A Meyer^{1

3}, Johnathan S Peters^{1

3}, Lucas L Figueiredo^{1

3}, Michael Sasner⁴, Paul R Territo^{1

3

6}, Stacey J Sukoff Rizzo⁷, Gregory W Carter⁴, Bruce T Lamb^{1

2

3}, Gareth R Howell⁴

Affiliations

¹ Indiana University School of Medicine, Indianapolis, IN, United States.
² Department of Radiology & Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, United States.
³ Stark Neurosciences Research Institute, Indianapolis, IN, United States.
⁴ The Jackson Laboratory, Bar Harbor, ME, United States.
⁵ Jackson Laboratory for Genomic Medicine, Farmington, CT, United States.
⁶ Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, United States.
⁷ Department of Medicine, Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.

Abstract

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 (Trem2^R47H ). We have termed this model, LOAD1. Additional variants including the M28L variant in phospholipase C Gamma 2 (Plcg2^M28L ) and the 677C > T variant in methylenetetrahydrofolate reductase (Mthfr ^{677C >} ^T ) were engineered by CRISPR onto LOAD1 to generate LOAD1.Plcg2^M28L and LOAD1.Mthfr ^{677C >} ^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.Plcg2^M28L 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.Mthfr ^{677C >} ^T animals fed with HFD. Furthermore, LOAD1.Plcg2^M28L but not LOAD1.Mthfr ^{677C >} ^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.

Keywords: Alzheime’s disease; diet; genetic risk alleles; obesity; predisposition; transcriptomics.

Copyright © 2022 Oblak, Kotredes, Pandey, Reagan, Ingraham, Perkins, Lloyd, Baker, Lin, Soni, Tsai, Persohn, Bedwell, Eldridge, Speedy, Meyer, Peters, Figueiredo, Sasner, Territo, Sukoff Rizzo, Carter, Lamb and Howell.