Researchers here outline a mechanism by which excess fat tissue may accelerate the onset and progression of Alzheimer's disease, by affecting the content of extracellular vesicles passing into the brain, that in turn increase the aggregation of misfolded amyloid-β that is characteristic of the early stages of the condition. Excess visceral fat also contributes to chronic inflammation via a range of different mechanisms, and Alzheimer's disease is clearly an inflammatory condition. As is usually the case, determining which mechanisms of disease are more or less important than the others is challenging. It is unclear how much weight to assign to this new discovery.
Obesity is a major modifiable risk factor for Alzheimer's disease (AD), but the mechanistic link between peripheral metabolic dysfunction and AD progression remains unclear. Adipose-derived extracellular vesicles (EVs) may penetrate the brain and alter lipid homeostasis, contributing to neurodegeneration. We isolated exosome-enriched EVs from subcutaneous and visceral fat of lean and obese individuals, followed by lipidomic profiling. An in vitro amyloid-β (Aβ) aggregation assay using purified Aβ40 and Aβ42 peptides was performed under lipid environments mimicking physiological and pathological states.
Our study shows that EVs from obese adipose tissue carry specific lipid species that modulate Aβ40 and Aβ42 aggregation in a lipid-type- and concentration-dependent manner. These findings provide compelling molecular evidence linking peripheral lipid imbalance to Aβ aggregation, suggesting that metabolic dysfunction associated with obesity may contribute to central amyloid pathology via adipose-derived EV lipids. Further in vivo validation is warranted to substantiate this proposed link. These findings support lipid-targeted strategies as potential therapeutics for neurodegenerative diseases.
Link: https://doi.org/10.1002/alz.70603
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