Identification of the Sites of Tau Hyperphosphorylation and Activation of Tau Kinases in Synucleinopathies and Alzheimer’s Diseases

Objective: Most neurodegenerative diseases contain hyperphosphorylated Tau [p-Tau]. We examined for the first time epitopes at which Tau is hyperphosphorylated in Parkinson’s disease, dementia with Lewy bodies and Alzheimer’s disease, and also select Tau kinases. Methods: Postmortem frontal cortex from Parkinson’s disease, dementia with Lewy bodies, Alzheimer’s disease and striata from Parkinson’s disease, were analyzed by immunoblots using commercially available antibodies against 20 different phospho-epitopes of Tau. Major Tau kinases were also screened. Results in diseased tissues were compared to nondiseased controls. Results: In Alzheimer’s disease, Tau was hyperphosphorylated at all the 20 epitopes of p-Tau. In dementia with Lewy bodies, p-Tau formation occurred at 6 sites sharing 30 % overlap with Alzheimer’s disease, while in Parkinson’s frontal cortex, an area which does not degenerate, Tau hyperphosphorylation was seen at just 3 epitopes, indicating 15 % overlap with Alzheimer’s disease. In Parkinson’s disease striatum, an area which undergoes considerable neurodegeneration, Tau was hyperphosphorylated at 10 epitopes, sharing 50 % overlap with Alzheimer’s disease. Between frontal cortex of Parkinson’s disease and dementia with Lewy bodies, there were only two p-Tau epitopes in common. In striata of Parkinson’s disease, there were 3 clusters of Tau hyperphosphorylated at 3 contiguous sites