Why do only some people develop Alzheimer's disease? Why do only some people with evidence of amyloid and tau protein aggregation in brain tissue also exhibit dementia? These are important questions. Researchers here provide evidence to suggest that whether or not tau protein is isomerized is relevant to the onset and progression of Alzheimer's disease. Isomers of the same molecule have the same molecular weight but a different structure and chemistry. Whether or not isomers of important proteins are present in significant numbers is not well studied in the context of neurodegenerative conditions; perhaps it should be. The researchers here suggest that reduced protein quality control due to faltering autophagy may be to blame for increased isomerization; where this fits into the bigger picture of Alzheimer's pathology is an open question.
Recent work has posited a connection between Alzheimer's disease (AD) and isomerization of amino acids in long-lived proteins, which may interfere with lysosomal digestion. Herein, we reanalyzed data originally recorded for global proteomic analysis to look for isomerized peptides, which occur as a result of spontaneous chemical modifications to long-lived proteins. Examination of a large set of human brain samples revealed a striking relationship between Alzheimer's disease (AD) status and isomerization of aspartic acid in a peptide from tau. Relative to controls, a surprising increase in isomer abundance was found in both AD samples.
To explore potential mechanisms that might account for these observations, quantitative analysis of proteins related to isomerization repair and autophagy was performed. Differences consistent with reduced autophagic flux in AD-related samples relative to controls were found for numerous proteins, including most notably p62, a recognized indicator of autophagic inhibition. These results suggest, but do not conclusively demonstrate, that lower autophagic flux may be strongly associated with loss of function in AD brains.
Link: https://doi.org/10.1...roteome.1c00558
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