Gut Acetic Acid Alleviates Cognitive Impairment by Inhibiting Tau Hyperphosphorylation via Regulating FFAR3/Erk Pathway in Chronic Cerebral Ischemia Mice.

Chronic cerebral ischemia is a significant contributor to cognitive impairment, which plays a crucial role in the pathogenesis of vascular dementia (VaD). While tau hyperphosphorylation is acknowledged as a critical risk factor, the precise mechanisms underlying this process remain poorly understood. Recent studies have indicated a significant correlation between low abundance of intestinal short-chain fatty acids (SCFAs) and tau hyperphosphorylation. In this study, we assessed neurological function in mice subjected to chronic cerebral ischemia through bilateral common carotid artery stenosis (BCAS) and in cells through oxygen-glucose deprivation (OGD). In our investigation, we observed cognitive deficits in chronic cerebral ischemia mice. This was accompanied by dysbiosis of the intestinal microbiota, markedly reduced levels of acetic acid (Ace), aberrant Erk activation, and increased tau hyperphosphorylation. Notably, supplementation with Ace exhibits a significant neuroprotective effect. Utilizing both BCAS mice and OGD cell models, our study elucidated that Ace can ameliorate cognitive impairment induced by chronic cerebral ischemia. The underlying mechanism may involve a reduction in tau hyperphosphorylation, potentially mediated through the inhibition of Erk activity via the free fatty acid receptor 3 (FFAR3)/Erk signaling pathway. This research provides novel insights into the pathophysiology of VaD resulting from chronic cerebral ischemia and offers potential therapeutic strategies for its clinical management, highlighting the significance of targeting metabolic dysregulation in the prevention and treatment of cognitive decline.