Bioenergetic impairment-induced Tau acetylation: Converging pathways in Alzheimer's disease

Alzheimer's disease (AD) is increasingly recognized as a metabolic disorder in which disruptions in cellular energy metabolism play a central role in its progression. The dysregulated metabolism of carbohydrates, proteins, fatty acids, and nucleic acids collectively impairs neuronal bioenergetics, leading to mitochondrial dysfunction and reduced ATP production. This impaired energy metabolism trigger a cascade of cellular stress responses, including endoplasmic reticulum (ER) stress, oxidative and inflammatory responses, and increased generation of amyloid-β (Aβ), thereby exacerbating neuronal vulnerability. A critical downstream consequence of bioenergetic failure is the altered epigenetic and post-translational regulatory enzymes, particularly the acetyltransferase EP300 and the NAD⁺-dependent deacetylases known as sirtuins. An imbalance in the activity of these enzymes promotes the abnormal tau acetylation, which disrupts tau-microtubule interactions and promotes tau aggregation, ultimately accelerating neurodegeneration. Emerging evidence suggests tau acetylation as a mechanistic link between metabolic dysfunction and hallmark pathological characteristics of AD, suggesting bioenergetic impairment directly regulate tau pathology. Thus, understanding the metabolic pathways that drive tau acetylation may offer new therapeutic targets aimed at restoring neuronal energy balance, re-establishing acetylation homeostasis, and potentially slowing the progression of AD.