Plcg2^M28Linteracts with high fat-high sugar diet to accelerate Alzheimer’s disease-relevant phenotypes in mice

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 a high fat/high sugar diet. We focused on three mouse models created through the IU/JAX/Pitt MODEL-AD Center, LOAD1, LOAD1. Plcg2 M28L and LOAD1. Mthfr 677C>T. At 2 months of age, animals were placed on a high fat/high sugar diet (HFD) that induces obesity, or a control diet (CD) that does not, until 12 months of age. Throughout the study, blood was collected to assess cholesterol and glucose. Positron emission tomography/computed tomography (PET/CT) was completed prior to sacrifice to image for glucose utilization and brain perfusion. At the completion of the study, blood and brains were collected for analysis. As expected, animals fed the HFD, regardless of genotype or sex, showed a significant increase in body weight compared to those fed the CD. Glucose and cholesterol increased as a function of HFD as well. Interestingly, LOAD1. Plcg2 M28L demonstrated an increase in microglia density as well as alterations in regional brain glucose and perfusion when on a HFD.These changes were not observed in LOAD1 or LOAD1. Mthfr 677C>T animals when fed a HFD . Furthermore, LOAD1. Plcg2 M28L but not LOAD1. Mthfr 677C>T or LOAD1 animals showed transcriptomics correlations to human AD modules.Our results show HFD affects brain health in a genotype-specific manner. Further insight into this process may have significant implications in the development of lifestyle interventions for treatment of AD.

In vivovalidation of late-onset Alzheimer’s disease genetic risk factors

“…The SNX1*D465N (rs1802376) variant locus is associated with AD (24) and SNX1 is involved in retromer function relevant to LOAD (30). PLCG2*M28L (rs61749044) has been associated with LOAD [https://www.biorxiv.org/content/10.1101/2020.05.19.104216v1, (24,31) and Plcg2 is a key protein in microglial activation in response to AD pathology (32). The SHC2*V433M (rs61749990) variant was identified in ADSP exomes and has been associated with neurodegeneration and neuron loss (33,34).…”

Genetic Variants of Phospholipase C-γ2 Confer Altered Microglial Phenotypes and Differential Risk for Alzheimer’s Disease

“…PLCG2 P522R and PLCG2 M28L mice were generated using CRISPR/cas9 endonuclease-mediated genome editing to introduce the mutations. The APOE4 gene sequence and TREM2 R47H mutation from the PLCG2 M28L mouse model (Oblak et al, 2022) were moved by crossing with B6 mice. These mice were maintained on the B6 background and crossed with 5xFAD mice to yield the 5xFAD; PLCG2 M28L and 5xFAD; PLCG2 P522R genotypes (5xFAD M28L and 5xFAD P522R ).…”