Branched-Chain Amino Acids Are Linked with Alzheimer’s Disease-Related Pathology and Cognitive Deficits

dc.creatorSiddik, Md abu Bakkar (TTU)
dc.creatorMullins, Caitlyn A (TTU)
dc.creatorKramer, Alyssa (TTTU)
dc.creatorShah, Harsha (TTU)
dc.creatorGannaban, Ritchel B (TTU)
dc.creatorZabet-Moghaddam, Masoud (TTU)
dc.creatorHuebinger, Ryan M
dc.creatorHegde, Vijay K (TTU)
dc.creatorMohanKumar, Sheba M. J.
dc.creatorMohanKumar, Puliyur S
dc.creatorShin, Andrew C (TTU)
dc.date.accessioned2023-03-01T17:55:16Z
dc.date.available2023-03-01T17:55:16Z
dc.date.issued2022
dc.description© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)en_US
dc.description.abstractAlzheimer’s disease (AD) is an irreversible neurodegenerative disorder with a complex pathophysiology. Type 2 diabetes (T2D) is a strong risk factor for AD that shares similar abnormal features including metabolic dysregulation and brain pathology such as amyloid and/or Tau deposits. Emerging evidence suggests that circulating branched-chain amino acids (BCAAs) are associated with T2D. While excess BCAAs are shown to be harmful to neurons, its connection to AD is poorly understood. Here we show that individuals with AD have elevated circulating BCAAs and their metabolites compared to healthy individuals, and that a BCAA metabolite is correlated with the severity of dementia. APPSwe mouse model of AD also displayed higher plasma BCAAs compared to controls. In pursuit of understanding a potential causality, BCAA supplementation to HT-22 neurons was found to reduce genes critical for neuronal health while increasing phosphorylated Tau. Moreover, restricting BCAAs from diet delayed cognitive decline and lowered AD-related pathology in the cortex and hippocampus in APP/PS1 mice. BCAA restriction for two months was sufficient to correct glycemic control and increased/restored dopamine that were severely reduced in APP/PS1 controls. Treating 5xFAD mice that show early brain pathology with a BCAA-lowering compound recapitulated the beneficial effects of BCAA restriction on brain pathology and neurotransmitters including norepinephrine and serotonin. Collectively, this study reveals a positive association between circulating BCAAs and AD. Our findings suggest that BCAAs impair neuronal functions whereas BCAA-lowering alleviates AD-related pathology and cognitive decline, thus establishing a potential causal link between BCAAs and AD progression.en_US
dc.identifier.citationSiddik MAB, Mullins CA, Kramer A, Shah H, Gannaban RB, Zabet-Moghaddam M, Huebinger RM, Hegde VK, MohanKumar SMJ, MohanKumar PS, Shin AC. Branched-Chain Amino Acids Are Linked with Alzheimer’s Disease-Related Pathology and Cognitive Deficits. Cells. 2022; 11(21):3523. https://doi.org/10.3390/cells11213523en_US
dc.identifier.urihttps://doi.org/10.3390/cells11213523
dc.identifier.urihttps://hdl.handle.net/2346/90855
dc.language.isoengen_US
dc.subjectglucose metabolismen_US
dc.subjectBCAAen_US
dc.subjectneurotransmittersen_US
dc.subjectAβ-42en_US
dc.subjectTauen_US
dc.subject5xFADen_US
dc.subjectAPP/PS1en_US
dc.subjectdiet restrictionen_US
dc.titleBranched-Chain Amino Acids Are Linked with Alzheimer’s Disease-Related Pathology and Cognitive Deficitsen_US
dc.typeArticleen_US

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