Spontaneous isomerization of tau is most prevalent in Alzheimer’s disease

Alzheimer's disease is the most common cause of dementia in humans and has been the subject of intense study for decades. Despite these efforts, the precise underlying cause or causes of Alzheimer's disease have remained elusive. Here we implement novel analysis of mass-spectrometry derived proteomics data to examine an understudied phenomenon related to Alzheimer's disease, isomerization of the protein tau. Isomerization is a spontaneous chemical modification that occurs in long-lived proteins and evolves most rapidly at aspartic acid. Recent results have demonstrated that isomerization of tau is more prevalent in Alzheimer's disease relative to healthy controls. To further map out the importance of tau isomerization in neurodegeneration, we examined its prevalence in several additional diseases by mining publicly available datasets and our own results, allowing for examination of Parkinson's disease, Lewy body dementia, vascular brain injury, and chronic traumatic encephalopathy. To evaluate the extent of tau isomerization in various locations within the brain in Alzheimer's disease, we examined samples from the frontal cortex, anterior cingulate gyrus, inferior parietal lobule, and caudate. Interestingly, our results demonstrate that significant isomerization of tau occurs only in individuals with Alzheimer's disease. In terms of localization, tau was easily detected in all regions of the brain, and tau isomerization was detected for Alzheimer's disease in all regions except the caudate. Importantly, tau isomerization can be easily and rigorously quantified from proteomics data. Comparison of the extent of tau isomerization with pre-mortem performance on the Mini-Mental State Examination revealed strong correlation. In addition to minimal abundance in other forms of neurodegeneration, tau isomerization was also low for a small number of the individuals designated to have Alzheimer's disease in our study, however consideration of other factors such as genetic predisposition, age, and mental acuity also differentiates these individuals. Importantly, the amount of tau isomerization observed in our studies does not correlate in any meaningful way with tau aggregation. Collectively, these observations suggest that tau isomerization derives from a different pathogenesis than other neurodegenerative markers, one that is only prevalent in Alzheimer's disease and may offer means for delineating the underlying causes of the disease.