The potentially protective role of an understudied tau isoform in Alzheimer’s disease

Abstract

AbstractBackgroundAs Alzheimer’s disease (AD) progresses, tau becomes abnormally aggregated and hyperphosphorylated in selective brain regions such as the cortex and hippocampus. Surprisingly, the cerebellum remains spared from tau pathology. Given this observation, we proposed to examine possible differences in the level of various tau isoforms in the cerebellum compared to the forebrain.MethodsWe first compared the transcript and protein levels of tau isoforms between the cerebellum and other brain regions (e.g., the cortex and hippocampus) using both mouse and human brain samples. Here, we discovered that “big tau”, an understudied tau isoform previously reported to be specifically expressed in the periphery, is highly elevated in the cerebellum compared to other brain regions. Next, we performed detergent fractionation using cells expressing mutant big tau or tau441 (the longest one of six major tau isoforms) to compare the aggregation propensity between the two tau isoforms. Lastly, to test this in an animal model, we injected a newborn wild‐type mice with adeno‐associated viruses (AAV) that express either mutant big tau or tau441. After aging the mice for 6 to 9 months, we examined their brains to analyze pathological changes associated with either of these two tau isoforms.ResultsWe found that the transcript level of big tau is significantly higher in the mouse cerebellum compared to the cortex and hippocampus. Using the total tau antibody and the novel mouse big tau‐specific antibody that we generated, we confirmed that big tau protein level is also significantly elevated in the cerebellum. We obtained similar results in human tissues as both the transcript and protein levels of big tau were higher in the cerebellum than the cortex. Interestingly, our fractionation experiment using cells revealed that big tau protein is significantly less likely to aggregate compared to tau441. Consistent with these results, big tau did not become pathologically aggregated or phosphorylated compared to tau441 in the AAV‐based mouse model.ConclusionBig tau has a substantially lower tendency to become pathologically aggregated or hyperphosphorylated. The higher level of big tau in the cerebellum may potentially protect this brain region from developing tau pathology in AD.