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.