Targeting tau acetylation in Alzheimer's disease: Molecular mechanisms, pathological consequences, and therapeutic opportunities of dietary phytochemicals.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, synaptic dysfunction, and neuronal loss. Emerging evidence identifies tau acetylation as a crucial post-translational modification that contribute significantly to tauopathies associated pathology in AD. Aberrant tau acetylation results in autophagy dysregulation, DNA damage, altered lipid metabolism, endoplasmic reticulum (ER) stress, and neuroinflammation ultimately leading to cognitive decline and neuronal death. Dysregulation of acetyltransferases such as p300/CBP and reduced deacetylase activity, including sirtuins, further promote pathological tau accumulation and propagation. Dietary phytochemicals have emerged as promising multi-targeted neuroprotective agents due to their antioxidant, anti-inflammatory, and epigenetic regulatory properties. Notably, studies investigating dietary phytochemicals that directly regulate tau acetylation remain very limited, making this an important and promising area for future research. Nevertheless, several dietary phytochemicals have been reported to modulate the activities of SIRT1 and EP300 across a range of experimental models and various disease conditions. Future investigations should focus on incorporating these dietary phytochemicals into experimental models of AD to elucidate their potential to modulate tau acetylation and associated pathogenic mechanisms. Such studies will provide critical insights into their therapeutic potential and may facilitate the development of novel phytochemical-based interventions for tau acetylation in AD. This review provides a comprehensive overview of the mechanisms by which tau acetylation contributes to AD pathology and highlights therapeutic opportunities of dietary phytochemicals.