Comorbid Alzheimer’s Disease Tau Isomerization

Alzheimer’s disease (AD) 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 including, Parkinson’s disease, Lewy body dementia, vascular brain injury, and chronic traumatic encephalopathy. To evaluate the extent of tau isomerization in the brain, we examined additional brain regions including, 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 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 its absence in other forms of neurodegeneration, tau isomerization was also minimal 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 could also be used to differentiate 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 unique to Alzheimer’s disease and may offer means for delineating the underlying causes of the disease.