Role of the metabolism of branched-chain amino acids in the development of Alzheimer's disease and other metabolic disorders

Baruh Polis, Abraham O. Samson

Research output: Contribution to journalReview articlepeer-review

83 Scopus citations

Abstract

Alzheimer's disease is an incurable chronic neurodegenerative disorder and the leading cause of dementia, imposing a growing economic burden upon society. The disease progression is associated with gradual deposition of amyloid plaques and the formation of neurofibrillary tangles within the brain parenchyma, yet severe dementia is the culminating phase of the enduring pathology. Converging evidence suggests that Alzheimer's disease-related cognitive decline is the outcome of an extremely complex and persistent pathophysiological process. The disease is characterized by distinctive abnormalities apparent at systemic, histological, macromolecular, and biochemical levels. Moreover, besides the well-defined and self-evident characteristic profuse neurofibrillary tangles, dystrophic neurites, and amyloid-beta deposits, the Alzheimer's disease-associated pathology includes neuroinflammation, substantial neuronal loss, apoptosis, extensive DNA damage, considerable mitochondrial malfunction, compromised energy metabolism, and chronic oxidative stress. Likewise, distinctive metabolic dysfunction has been named a leading cause and a hallmark of Alzheimer's disease that is apparent decades prior to disease manifestation. State-of-the-art metabolomics studies demonstrate that altered branched-chain amino acids (BCAAs) metabolism accompanies Alzheimer's disease development. Lower plasma valine levels are correlated with accelerated cognitive decline, and, conversely, an increase in valine concentration is associated with reduced risk of Alzheimer's disease. Additionally, a clear BCAAs-related metabolic signature has been identified in subjects with obesity, diabetes, and atherosclerosis. Also, arginine metabolism is dramatically altered in Alzheimer's disease human brains and animal models. Accordingly, a potential role of the urea cycle in the Alzheimer's disease development has been hypothesized, and preclinical studies utilizing intervention in the urea cycle and/or BCAAs metabolism have demonstrated clinical potential. Continual failures to offer a competent treatment strategy directed against amyloid-beta or Tau proteins-related lesions, which could face all challenges of the multifaceted Alzheimer's disease pathology, led to the hypothesis that hyperphosphorylated Tau and deposited amyloid-beta proteins are just hallmarks or epiphenomena, but not the ultimate causes of Alzheimer's disease. Therefore, approaches targeting amyloid-beta or Tau are not adequate to cure the disease. Accordingly, the modern scientific vision of Alzheimer's disease etiology and pathogenesis must reach beyond the hallmarks, and look for alternative strategies and areas of research.

Original languageEnglish
Pages (from-to)1460-1470
Number of pages11
JournalNeural Regeneration Research
Volume15
Issue number8
DOIs
StatePublished - Aug 2020

Bibliographical note

Publisher Copyright:
© 2020 Wolters Kluwer Medknow Publications. All rights reserved.

Funding

Author contributions: Both authors equally contributed to the drafting of this article, critically analyzed and reviewed the existing literature, and approved the final version of the manuscript. Conflicts of interest: The authors declare no conflicts of interest. Financial support: This work was supported by a Marie Curie CIG Grant 322113, a Leir Foundation Grant, a Ginzburg Family Foundation Grant, and a Katz Foundation Grant to AOS. Copyright license agreement: The Copyright License Agreement has been signed by both authors before publication. Plagiarism check: Checked twice by iThenticate. Peer review: Externally peer reviewed. Open access statement: This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. Open peer reviewers: Hans-Gert Bernstein, University of Magdeburg, Germany; Jason Eriksen, University of Houston, USA. Additional file: Open peer review reports 1 and 2. Funding: This work was supported by a Marie Curie CIG Grant 322113, a Leir Foundation Grant, a Ginzburg Family Foundation Grant, and a Katz Foundation Grant to AOS.

FundersFunder number
Ginzburg Family Foundation
Leir Foundation
Jerold B. Katz Foundation
Seventh Framework Programme322113
Marie Curie

    Keywords

    • BCAAs
    • arginase
    • arginine
    • branched-chain aminotransferase
    • dementia
    • mTOR
    • norvaline
    • urea cycle
    • valine

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