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Accumulation of tau fibrils characterizes a group of neurodegenerative diseases known as tauopathies, which include frontotemporal dementia (FTD) and Alzheimer disease (AD), but the mechanisms underlying tau neurotoxicity are unclear. A new study suggests that acetylation of soluble tau species could be an early stage in disease and that inhibition of this process could be a potential therapeutic strategy.

Hyperphosphorylation of tau is a well-known post-translational modification that can lead to accumulation of insoluble neurofibrillary tangles in tauopathies. However, recent evidence suggests that such tau fibrils are not the pathogenic culprit and points instead to soluble tau species. Acetylation of soluble tau has important effects on the properties of tau, including its stability and aggregation, and acetylated tau is upregulated in AD brain lysates. For the current study, Min et al. sought to investigate the possible link between tau acetylation and neurodegeneration.

To determine which tau residues are acetylated in disease, the researchers performed liquid chromatography and mass spectrometry on tau extracted from soluble lysates from human brains. They found the residue lysine 174 (K174) to be acetylated in AD brains, including in samples from individuals with early-stage disease.

Next, the authors studied the tau mutants K174Q, which mimics the effect of acetylation at this residue, and K174R, which cannot be acetylated and therefore mimics deacetylated wild-type tau. In rat primary neurons, K174Q had a longer half-life than K174R or wild-type tau, indicating that acetylation reduces tau turnover. Moreover, following injection into the hippocampi of mice, K174Q accumulated at higher concentrations in this brain region than did the other tau species.

What effect does acetylated tau have in the brain? In mice, overexpression of K174Q tau in the hippocampus by adenoviral delivery led to significantly more atrophy in this brain region after 3 months than did overexpression of wild-type or K174R tau. In addition, mice overexpressing K174Q performed worse in functional tests of spatial learning and memory retention.

Last, the authors investigated the effect of inhibitors of p300, which is an acetyltransferase responsible for the acetylation of tau. In neuronal cell culture, the p300 inhibitor salicylate (a nonsteroidal anti-inflammatory) reduced the levels of tau acetylation at K174 and enhanced tau turnover. In the PS19 mouse model of FTD, oral administration of salsalate — a prodrug of salicylate used to treat rheumatoid arthritis — led to inhibition of brain p300 and a reduction in acetylated tau. Importantly, treatment with salsalate for about 70 days prevented hippocampal atrophy and improved spatial memory relative to vehicle-treated PS19 mice. Moreover, inhibition of tau acetylation seemed to be crucial for the protective effects of salsalate, as K174Q-expressing mice still underwent hippocampal atrophy following administration of the drug.

The authors note that effects of p300 inhibition besides reduction of tau acetylation, such as enhanced autophagy, could have contributed to the beneficial effects observed. Additionally, given the role of p300 in several important biological processes, caution would be needed to ensure only partial inhibition.

Together, these findings highlight tau acetylation as a pathogenic step in tauopathies such as AD and suggest a new therapeutic approach for these currently intractable diseases.