Basic Science and Pathogenesis

Alzheimer's disease (AD) is a complex disorder involving multiple cellular and molecular mechanisms. Recent evidence suggests that metabolic alterations play a crucial role in AD progression. Likewise, diabetes and obesity-two major metabolic diseases-are well-established risk factors for AD. These conditions are associated with a significant expansion of visceral adipose tissue. Here, we hypothesize that visceral adipose tissue may act as a key mediator between peripheral metabolic dysfunction and brain illnesses.

We used histological stains, immunohistochemistry, and biochemical assays to analyze changes in visceral adipose tissue from WT, db/db, and WT mice subjected to a high-fat diet (HFD). Additionally, we performed adipose tissue transplants from db/db donors into 3xTg-AD mice and from HFD-fed WT donors into Tau P301S mice to evaluate potential alterations in tau pathology in these distinct AD models.

Our study shows that 3xTg-AD mice receiving fat pads from db/db donors exhibited a significant increase in tau pathology, driven by elevated p25/p35 expression, compared to 3xTg-AD mice receiving fat from standard-diet WT mice. This tau accumulation was associated with increased IL-1β levels and robust microglial activation. Similarly, Tau P301S mice transplanted with fat from HFD-fed WT donors also displayed exacerbated tau pathology and neuroinflammation, indicating that metabolic dysfunction induced major changes in neuroinflammation that contributed to tau pathology.

Overall, our study highlights a novel interplay between AD and metabolic disorders, demonstrating that visceral adipose tissue from both genetically obese/diabetic and diet-induced obese mice exacerbates tau pathology via immune system activation. These findings reinforce the role of metabolic dysfunction in AD and suggest visceral adipose tissue as a potential target for therapeutic intervention.