Tau acetylation
Acetylation of tau at lysine 280 has been recognized as a significant determinant of the molecular etiology of Alzheimer’s disease (AD)81. Emerging scholarly investigations have provided compelling evidence that tau acetylation may precede tau hyperphosphorylation, thus potentially serving as the primary catalyst for neuronal degeneration in the early stages of Alzheimer’s disease (AD). The presence of acetylated tau 280 was observed in all instances of early Alzheimer’s disease (AD) by Lucke-Wold et al., thereby supporting the hypothesis that tau acetylation may occur prior to phosphorylation and exerts a pivotal influence on the process of neurodegeneration.
The process of acetylation of tau protein involves the addition of acetyl groups to specific lysine residues82. Notably, lysine 280, which is located within the microtubule-binding motif, has been identified as a prominent site for tau acetylation. Acetylation has been observed to induce modifications in the functionality of tau protein, thereby facilitating the progression of pathological tau aggregation and hindering its interactions with microtubules. Cohen et al. and Trzeciakiewicz et al. elucidated the detrimental effects of acetylation at K280/K281 on tau-mediated microtubule stabilization, while concurrently promoting tau aggregation18,82. Other studies have found that specifically, acetylation of tau proteins at the lysine 280 residue, plays a major role in propelling AD pathogenesis. Detailed studies by Irwin et al., showed that acetylated-tau pathology played an equally significant role in AD pathogenesis as hyperphosphorylated tau. Furthermore, significant concentrations of acetylated-tau were found in all stages of AD pathogenesis, with higher concentrations correlated with later stages of AD, as observed in post-mortem AD patient’s brains. Recent studies have posited that tau acetylation at lysine 280 likely contributes to AD pathogenesis by limiting tau solubility, interfering with normal microtubule assembly mechanics, and promoting the formation of tau fibrils. In the study by Caballero et al., tau acetylation was correlated with disrupting chaperone-mediated autophagy, thus stimulating pathological tau pathways. These findings provide compelling evidence that the process of tau acetylation disturbs the regular physiological operations of tau, thereby playing a contributory role in the genesis of tau aggregates commonly observed in Alzheimer’s disease (AD)Thus, the involvement of tau acetylation in the progression of Alzheimer’s disease (AD) has been established. Experimental investigations utilizing viral-transduced and transgenic mouse models have provided evidence that replication of tau acetylation at distinct sites elicits AD-like phenotypes, such as synaptic dysfunction, neuronal degeneration, and cognitive deficits. The potential therapeutic strategy of modulating the tau acetylation machinery to restrict the acetylation of residues K280 and K281 holds promise for the cessation of tau aggregation and subsequent neurodegeneration observed in Alzheimer’s disease (AD)18,83,84. Deacetylases, such as HDAC6 and SIRT1, have been identified as enzymatic entities capable of catalyzing the deacetylation process of tau18,82,85. The augmentation of deacetylase activity or the suppression of acetyltransferase activity holds promise for the restoration of physiological tau function and the prevention of pathological tau aggregation.
Studies have found that salsalate can prohibit tau acetylation by interfering with p300 acetyltransferase activities and compromising the structural integrity of K174 acetylation sites in transgenic mouse models. Furthermore, salsalate has significant efficacy in mitigating atrophy in hippocampal regions and preventing memory deficits. Although positive results were found in in vitro salsalate administration, its efficacy was limited in a phase 1 clinical trial. Results from the clinical trial showed that even though salsalate had optimal biocompatibility in patients, their cognitive performance was not significantly improved upon salsalate administration. Researchers hypothesized that salsalate’s efficacy was likely limited by the suboptimal penetration of salsalate into the patient’s brains. This limitation could be overcome by encapsulating salsalate within nanoparticulate systems, as extensive studies have shown that optimally functionalized nanoparticles often have significantly higher penetration capabilities in biological tissue, when compared to free compounds. However, to definitively establish this, further research is required.
In Alzheimer’s disease (AD) research, tau acetylation has garnered considerable attention as a notable factor in the development and progression of the disease18,81–83. Consequently, directing interventions towards the modulation of acetylation machinery presents a promising avenue for therapeutic exploration, with the potential to revolutionize the treatment of AD and ameliorate its neurodegenerative consequences. Further investigation is warranted to attain a comprehensive understanding of the intricacies of tau acetylation and its plausible therapeutic ramifications.