University of Kentucky researchers link new, unmutated protein to dementia

Newswise – LEXINGTON, Kentucky (February 2, 2022) – A team of researchers from the Sanders-Brown Center on Aging (SBCoA) at the University of Kentucky is working to identify new proteins that are destructive to the brain. They know that about 25% of people and 50% of people with Alzheimer’s disease have the genetic mutation APOE ε4 allele – a known risk factor for the disease.

Thanks to a recent study, researchers were surprised to find that even in the brains of patients without the disease-causing mutation, ApoE proteins were enhanced in dementia. Their findings appear in The American Journal of Pathology, published by Elsevier.

“Dementia is very complex, but you can simplify it: the disease is caused by ‘gloppy proteins’ in the brain,” said lead researcher Peter T. Nelson, MD, Ph.D., director of neuropathology at SBCoA and Professor in the UK Department of Pathology. “I don’t care; these “sticky” misfolded proteins often end up destroying brains, minds, memories and everything else for millions of people with dementia. We want to understand specifically which proteins are the problem.

Investigators examined 40 participants from the University of Kentucky Alzheimer’s Center autopsy cohort – Kentucky residents who agreed to donate their brains at the time of their death. Subjects ranged from cognitively normal dementia to severe dementia. Although previous studies have examined the human amygdala proteome, none have reported a sample of this size with subjects with dementia and control subjects for comparison.

As expected, portions of proteins previously associated with neurodegenerative diseases have been found in the brains of dementia patients, including proteins called Tau (associated with neurofibrillary tangles), Aβ (associated with amyloid plaques), and α-Synuclein (associated with Lewy body disease). Ass and α-Synuclein was strongly correlated with the clinical diagnosis of dementia. Tau and Aβ proteins, but not α-Synuclein was occasionally detectable in cognitively normal subjects and in those with mild cognitive impairment. Overall, Nelson says the results were in line with their expectations.

“Like many great scientific stories, this is not entirely new. Other researchers have produced similar results,” Nelson said. “However, this finding strongly underscores the potential for ApoE to promote dementia, even in people who don’t carry the ‘bad’ gene.”

The data revealed a close correlation between the diagnosis of dementia and the detection of ApoE peptides in the brain. The correlation with dementia for ApoE was even stronger than that observed for Tau, Aβ or α-Synuclein. Researchers found that ApoE peptides were significantly enriched even in dementia patients who lacked the APOE ε4 allele. The results highlight that the ApoE protein may play an active role in the disease, rather than simply being an “upstream” genetic risk factor.

“Our study adds to an evolutionary appreciation of multiple misfolded proteins in the human brain and advances the field by highlighting that ApoE may be an important contributor to the prototype of dementia, even in people who lack the version pathogen of APOE gene,” Nelson said. “Even in people without APOE ε4 allele, ApoE may indeed be one of the most influential “gloppy proteins” in the aging brain. »

The research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under award numbers P30AG072946, R01AG042419, R01AG042475, R01AG061111, R01 AG057187 R21AG061551, R01AG060056, R01AG062550; the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award numbers RF1NS118584 and R21NS095299; and the National Center for Research Resources of the National Institutes of Health under award number S10 RR029127. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

This material is based on work supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. The opinions expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States Government.

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