Tauopathies, including frontotemporal dementia (FTD) and Alzheimer’s disease (AD), are neurodegenerative diseases in which tau fibrils accumulate. Recent evidence supports soluble tau species as the major toxic species. How soluble tau accumulates and how it causes neurodegeneration remains unclear. Here we identified tau acetylation at K174 as an early change in AD brains and as a critical determinant in tau homeostasis and toxicity in mice. An acetyl-mimicking mutant (K174Q) slows down tau turnover and induces cognitive deficits in vivo. The acetyltransferase p300-induced tau acetylation is inhibited by a prescription drug salsalate/salicylate, which enhances tau turnover and reduces tau levels. In the PS19 transgenic mouse model of FTD, administering salsalate after disease onset inhibited p300 activity, lowered ac-K174 and total tau levels, rescued tau-induced memory deficits and prevented hippocampal atrophy. The tau-lowering and protective effects of salsalate/salicylate are diminished in neurons expressing K174Q tau. Targeting tau acetylation could be a new therapeutic strategy against human tauopathies.

The BTBR T+tf/J inbred mouse strain displays a variety of persistent phenotypic alterations similar to those exhibited in autism spectrum disorders (ASDs). The unique genetic background of the BTBR strain is thought to underlie its lack of reciprocal social interactions, elevated repetitive self-directed grooming, and restricted exploratory behaviors. In order to clarify the existence, range, and mechanisms of abnormal repetitive behaviors within BTBR mice, we performed detailed analyses of the microstructure of self-grooming patterns and noted increased overall grooming, higher percentages of interruptions in grooming bouts and a concomitant decrease in the proportion of incorrect sequence transitions compared to C57BL/6J inbred mice. Analyses of active phase home-cage behavior also revealed an increase in stereotypic bar-biting behavior in the BTBR strain relative to B6 mice. Finally, in a novel object investigation task, the BTBR mice exhibited greater baseline preference for specific unfamiliar objects as well as more patterned sequences of sequential investigations of those items. These results suggest that the repetitive, stereotyped behavior patterns of BTBR mice are relatively pervasive and reflect both motor and cognitive mechanisms. Furthermore, other pre-clinical mouse models of ASDs may benefit from these more detailed analyses of stereotypic behavior.

The core symptoms of autism spectrum disorder (ASD) include deficits in social interaction, impaired communication, and repetitive behaviors with restricted interests. Mouse models with behavioral phenotypes relevant to these core symptoms offer an experimental approach to advance the investigation of genes associated with ASD. Previous findings demonstrate that BTBR T+ tf/J (BTBR) is an inbred mouse strain that shows robust behavioral phenotypes with analogies to all three of the diagnostic symptoms of ASD. In the present study, we investigated the expression of social behaviors in a semi-natural visible burrow system (VBS), during colony formation and maintenance in groups comprising three adult male mice of the same strain, either C57BL/6J (B6) or BTBR. For comparative purposes, an extensively investigated three-chambered test was subsequently used to assess social approach in both strains. The effects of strain on these two situations were consistent and highly significant. In the VBS, BTBR mice showed reductions in all interactive behaviors: approach (front and back), flight, chase/follow, allo-grooming and huddling, along with increases in self-grooming and alone, as compared to B6. These results were corroborated in the three-chambered test: in contrast to B6, male BTBR mice failed to spend more time in the side of the test box containing the unfamiliar CD-1 mouse. Overall, the present data indicates that the strain profile for BTBR mice, including consistent social deficits and high levels of repetitive self-grooming, models multiple components of the ASD phenotype.