Isomerization of Tau May be Involved in Alzheimer's Disease

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.



Hi Reason, if this article about Viagra is confirmed, blood flow to the brain may be highly correlated to may of the more direct contributors to Alzheimers disease. Then, other mechanisms that contribute to blood flow to the brain may also have explanations, like exercise and clear arteries.

Posted by: Thomas Mark Schaefer at December 8th, 2021 2:20 PM

Quite interesting. There are a lot of reasons to uptegulate Autophagy in aging individuals. This is a biggie. There is enough evidence of multiple benefits without downsides to focus on this on a regular basis. Rapamycin, resveratrol, and polyamines are autophagic inductors clinically available that could improve age-related disorders. Fasting seems to be the only sure fire way to get this going. LEF has worked with Insilico to identify other compounds.
Here an interesting article

Posted by: august33 at December 9th, 2021 10:38 PM

@ Thomas Mark
Might work. Yesterday, on the radio there were all kind of silly jokes about regaining sexual activity before the memory...

there were a couple of articles where down-regulating autophagy was slowing some tissue decays

Posted by: Cuberat at December 10th, 2021 2:48 PM

@Thomas, Cube Rat
Hypertension, particularly midlife high blood pressure, has been related to a higher risk of cognitive decline and dementia, including Alzheimer disease.
Sildenafil (Viagra) is technically hypertension medication.
'Sildenafil started clinical development as an agent for the treatment of hypertension and angina, and subsequently evolved into a revolutionary new oral treatment for erectile dysfunction. Sildenafil was then further developed to become a much-needed new oral treatment for pulmonary arterial hypertension, and has also been shown to be effective in treating severe Raynaud's phenomenon associated with systemic sclerosis and digital ulceration. Later investigative studies have suggested that sildenafil also has promise in the treatment of respiratory disorders with ventilation/perfusion mismatch, congestive cardiac failure, hypertension and even stroke.'

Posted by: Jones at December 11th, 2021 4:29 AM
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