Isomerization and Autolysis at Specific Amino Acid Residues of the Tau Protein and its Relations to Alzheimer's Disease

Abstract

Alzheimer's Disease is the most common form of dementia that more than 5 million Americans are suffering from. With no known cure and no known cause, it is an urgent matter that researcher's are desperately attempting to tackle. Alzheimer's disease is clinically characterized by memory loss and histopathologically characterized by the high prevalence of amyloid plaques and neurofibrillary tangles (tau tangles). In a healthy brain, the tau protein performs the role of stabilizing microtubules in healthy neurons. However, due to their long turn-over rates, they are susceptible to many non-enzymatic, post-translational protein modifications such as racemization and isomerization. While in many cases aged or non-enzymatically damaged proteins can be repaired or replaced, some changes can inhibit protein turnover resulting in an accumulation of damaged protein over time. One of the modifications that very-long lived proteins have been shown to undergo is racemization of aspartic acid and asparagine residues to the non-natural D-form from the common L-form via succinimide intermediate. In this study we have employed quantitative label-free mass spectrometry to study isomerization/racemization reactions site specifically in the repeat-1 domain of Tau protein. We found that Asp-265 isomerizes into four different isoforms. We also found that the Tau peptide undergoes an auto-catalytic cleaveage without the use of a protease. A possible mechanism for the formation of the four isomers is proposed. This data may provide useful information on the in vivo rates of tau racemization, providing insights into the mechanisms and potentially opening a door to finding biomarkers for Alzheimer's disease.