Disease-associated astrocytes and microglia markers are upregulated in mice fed high fat diet

Abstract

High-fat diet (HFD) is associated with Alzheimer’s disease (AD) and type 2 diabetes risk, which share features such as insulin resistance and amylin deposition. We examined gene expression associated with astrocytes and microglia since dysfunction of these cell types is implicated in AD pathogenesis. We hypothesize gene expression changes in disease-associated astrocytes (DAA), disease-associated microglia and human Alzheimer’s microglia exist in diabetic and obese individuals before AD development. By analyzing bulk RNA-sequencing (RNA-seq) data generated from brains of mice fed HFD and humans with AD, 11 overlapping AD-associated differentially expressed genes were identified, including Kcnj2, C4b and Ddr1, which are upregulated in response to both HFD and AD. Analysis of single cell RNA-seq (scRNA-seq) data indicated C4b is astrocyte specific. Spatial transcriptomics (ST) revealed C4b colocalizes with Gfad, a known astrocyte marker, and the colocalization of C4b expressing cells with Gad2 expressing cells, i.e., GABAergic neurons, in mouse brain. There also exists a positive correlation between C4b and Gad2 expression in ST indicating a potential interaction between DAA and GABAergic neurons. These findings provide novel links between the pathogenesis of obesity, diabetes and AD and identify C4b as a potential early marker for AD in obese or diabetic individuals.

A review and analysis of key biomarkers in Alzheimer’s disease

“… Sirkis et al (2023) explores the association of early-onset Alzheimer’s disease (EOAD) with specific peripheral immune signatures, and single-cell RNA sequencing identified significant expansion of a CD4 T cell termed interferon (IFN) signaling-associated gene (ISAG) hi T cells. Lin et al (2023) has explored the association between high-fat diet and AD and T2D. Analysis of single-cell RNA-seq (scRNA-seq) data indicated C4b is astrocyte-specific.…”

“…The altered expression of iron death-related DEGs affected the infiltration of specific immune cell types. Non-coding RNAs (ncRNAs) are involved in ferroptosis and AD progression, Tan et al (2023) identified 5 AD and ferroptosis-related hub genes, and constructed a novel ferroptosis-related signature models including mRNAs, miRNAs and lncRNAs. Deng et al (2022) screen correlative ferroptosis-related genes (FRGs) in the progress of AD by logistic regression.…”

“…Notably, the hub gene CXCR4 emerged as a potential target for 20 different drugs. Tang et al (2023) identified 12 DEGs that were significant in AD and epilepsy, SCN2A, GRIA1, and KCNJ9 were the hub genes with high connectivity. Wang X.-D. et al ( 2021) captured hub genes of AD-and epilepsy-associated gene co-expression modules by weighted key driver analysis.…”

Obesity-induced blood-brain barrier dysfunction: phenotypes and mechanisms

“…This phenotypic shift was observable early during HFD feeding, even preceding substantial weight gain. Lin et al [ 133 ] elucidates the upregulation of disease-associated astrocyte (DAA) and microglia markers in response to an 12 w-HFD that are similar to the pathogenesis of Alzheimer’s disease. providing a direct link between dietary habits, neuroinflammation, and neurodegeneration.…”

Bridging metabolic syndrome and cognitive dysfunction: role of astrocytes

“…HFD-induced hypothalamic neuroinflammation, insulin resistance status, and glucolipid metabolism (173). HFD induces upregulation of hypothalamic potassium inwardly rectifying channel subfamily J member 2 Gene (Kcnj2), Complement 4b (C4b) and discoidin domain receptor 1 (Ddr1) and co-localizes with GFAP, and is therefore considered an early marker of obesity and diabetesrelated cognitive dysfunction (174). Secretion of inflammatory factors by astrocytes is associated with synaptic loss.…”