Diet-Induced Neuroinflammation: Understanding its Role in Brain Aging and Dementia Risk

Preclinical data show chronic high‑fat feeding produces region‑specific microglial activation and neuroinflammation — a high‑fat diet mouse study with direct implications for dementia risk.

The team localized transcriptional inflammation to neural centers controlling metabolism and memory, a signal that supports counseling patients about dietary risk factors as part of dementia prevention strategies.

Region‑resolved transcriptomics provide microglia‑specific transcriptional evidence that extends beyond prior systemic descriptions of metabolic inflammation. The neuroimmune response was not uniform: diet‑related signatures varied by brain region, suggesting regional vulnerability may underlie distinct cognitive and metabolic phenotypes and refining how clinicians might frame risk.

In male C57BL/6J mice exposed to chronic high‑fat feeding, investigators combined microglial enrichment with region‑specific RNA sequencing across cortex, hippocampus, hypothalamus and cerebellum to map transcriptional changes. At longer exposure, the cortex showed the most differentially expressed genes (≈68 DEGs), followed by hippocampus (≈42 DEGs) and hypothalamus (≈37 DEGs); the cerebellum showed minimal lasting changes. Many DEGs were microglial activation–linked, giving a plausible cellular mechanism for how diet perturbs brain homeostasis.

Pathway analysis repeatedly implicated NF‑kappaB signaling and broad inflammatory programs in microglial signatures after prolonged high‑fat exposure. Sustained microglial activation can impair synaptic maintenance, reduce clearance of protein and lipid debris, and alter neuronal–glial metabolic coupling — processes that accelerate neuroaging and increase long‑term neurodegenerative risk. The data point to a feed‑forward trajectory in which chronic high‑fat intake elevates risk for progressive brain dysfunction.