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Western Diet-induced Visceral Adipose Tissue Inflammation Promotes Alzheimer's Disease Pathology via Microglial Activation in a Mouse Model

ABSTRACT: Introduction: Western diet (WD)-induced visceral adipose tissue (VAT) inflammation is characterized by adipocyte hypertrophy, hypoxia, and apoptosis. Epididymal white adipose tissue (eWAT), a representative VAT depot in rodents, plays a central role in WD-induced inflammation by secreting pro-inflammatory cytokines that contribute to systemic and neuroinflammation. However, the mechanistic link between WD-driven eWAT inflammation and Alzheimer’s disease (AD) pathology remains unclear. Methods: WD feeding for 20 weeks was conducted to evaluate its effects on AD-related neuroinflammation and pathology in mice. Cerebral glucose metabolism was assessed using F-18 FDG-PET. RNA sequencing of eWAT and plasma cytokine profiling identified inflammation-associated factors. In vitro assays were performed to examine the effects of these cytokines on microglial activation, neuronal viability, and IL-6/STAT3 signaling. Results: WD group exhibited significantly increased levels of neuroinflammatory markers and increased hippocampal levels of AD-related proteins including amyloid-beta oligomers, amyloid precursor protein, and phosphorylated tau. Additionally, F-18 FDG PET imaging revealed reduced glucose metabolism in the thalamus and hippocampus of WD group compared to controls. RNA sequencing of eWAT and cytokine profiling of plasma identified CCL8, CCL9, CXCL13, and IL-18 as significantly elevated pro-inflammatory cytokines. In vitro analyses demonstrated that these eWAT-associated cytokines directly activate microglial cells via the IL-6/STAT3 signaling pathway, promoting hippocampal neuronal death. Discussion: These findings elucidate a critical pathway through which WD-induced eWAT inflammation exacerbates AD pathology through a systemic–to–neuroinflammation axis, highlighting the therapeutic potential of targeting eWAT-associated cytokines to mitigate diet-associated AD progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE307622 | GEO | 2025/10/31

REPOSITORIES: GEO

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Project description:Alzheimer's disease (AD) is a severe neurodegenerative disorder. Clinical trials to identify agents to treat AD have failed, and its underlying molecular pathology and etiology remain elusive. Neuroinflammation is thought to play a key role in the progression of AD. Emerging evidence has identified lower Nicotinamide adenine dinucleotide (NAD+) levels as a major factor in neurodegeneration, especially in AD. NAD+ is an important metabolite in all human cells, as it is at the convergence of many central processes in cellular and mitochondrial maintenance, including DNA repair and mitophagy (the degradation of damaged mitochondria). Our previous work found that treatment of 3xTgAD mice with an NAD+ precursor, nicotinamide riboside (NR), can improve key AD features including tau phosphorylation and learning deficits in mice. Here we used the APP/PS1 AD mouse model to interrogate the effect of NR on neuroinflammation. Microarray analysis revealed major changes in pathways and genes associated with inflammation and the APP/PS1 mice had lower NAD+ levels than WT mice. Thus, seven months old mice were treated with NR for five months and their NAD+/NADH ratio increased. Brain neuroinflammation decreased as determined by decreased activation of astrocytes and microglia, decreased pro-inflammatory cytokines and chemokines in the brains of the APP/PS1 mice. NR decreased neuroinflammation by lowering the NLRP3 inflammasome and NF-κB pathways. NR also attenuated DNA damage and apoptosis in the AD mouse brains. NR dramatically decreased senescence in the hippocampus and cortex of AD mice, relative to controls. Recent studies suggest that cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) activation are associated with DNA damage and senescence. cGAS-STING was activated in AD mice and decreases after NR treatment. Suggesting that NR can diminish neuroinflammation and senescence through the cGAS-STING pathway. NR treatment also greatly improved cognition and synaptic function in the APP/PS1 mice. We propose that the cGAS-STING pathway should be evaluated as a potential novel therapeutic target in AD.

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Western Diet-induced Visceral Adipose Tissue Inflammation Promotes Alzheimer's Disease Pathology via Microglial Activation in a Mouse Model

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