Branched-Chain Amino Acids Are Linked with Alzheimer’s Disease-Related Pathology and Cognitive Deficits
Alzheimer’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 eviden...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/21/3523 |
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| author | Md Abu Bakkar Siddik Caitlyn A. Mullins Alyssa Kramer Harsh Shah Ritchel B. Gannaban Masoud Zabet-Moghaddam Ryan M. Huebinger Vijay K. Hegde Sheba M. J. MohanKumar Puliyur S. MohanKumar Andrew C. Shin |
| author_facet | Md Abu Bakkar Siddik Caitlyn A. Mullins Alyssa Kramer Harsh Shah Ritchel B. Gannaban Masoud Zabet-Moghaddam Ryan M. Huebinger Vijay K. Hegde Sheba M. J. MohanKumar Puliyur S. MohanKumar Andrew C. Shin |
| author_sort | Md Abu Bakkar Siddik |
| collection | DOAJ |
| description | Alzheimer’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. APP<sub>Swe</sub> 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. |
| first_indexed | 2024-03-09T19:11:46Z |
| format | Article |
| id | doaj.art-e239139448ad4a719c9e0f12d92acc93 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T19:11:46Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-e239139448ad4a719c9e0f12d92acc932023-11-24T04:10:09ZengMDPI AGCells2073-44092022-11-011121352310.3390/cells11213523Branched-Chain Amino Acids Are Linked with Alzheimer’s Disease-Related Pathology and Cognitive DeficitsMd Abu Bakkar Siddik0Caitlyn A. Mullins1Alyssa Kramer2Harsh Shah3Ritchel B. Gannaban4Masoud Zabet-Moghaddam5Ryan M. Huebinger6Vijay K. Hegde7Sheba M. J. MohanKumar8Puliyur S. MohanKumar9Andrew C. Shin10Obesity and Metabolic Health Laboratory, Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, TX 79409, USANeurobiology of Nutrition Laboratory, Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, TX 79409, USANeurobiology of Nutrition Laboratory, Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, TX 79409, USANeurobiology of Nutrition Laboratory, Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, TX 79409, USANeurobiology of Nutrition Laboratory, Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, TX 79409, USACenter for Biotechnology & Genomics, Texas Tech University, Lubbock, TX 79409, USADepartment of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USAObesity and Metabolic Health Laboratory, Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, TX 79409, USADepartment of Veterinary BioSciences and Diagnostic Imaging, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USADepartment of Veterinary BioSciences and Diagnostic Imaging, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USANeurobiology of Nutrition Laboratory, Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, TX 79409, USAAlzheimer’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. APP<sub>Swe</sub> 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.https://www.mdpi.com/2073-4409/11/21/3523glucose metabolismBCAAneurotransmittersAβ-42Tau5xFAD |
| spellingShingle | Md Abu Bakkar Siddik Caitlyn A. Mullins Alyssa Kramer Harsh Shah Ritchel B. Gannaban Masoud Zabet-Moghaddam Ryan M. Huebinger Vijay K. Hegde Sheba M. J. MohanKumar Puliyur S. MohanKumar Andrew C. Shin Branched-Chain Amino Acids Are Linked with Alzheimer’s Disease-Related Pathology and Cognitive Deficits Cells glucose metabolism BCAA neurotransmitters Aβ-42 Tau 5xFAD |
| title | Branched-Chain Amino Acids Are Linked with Alzheimer’s Disease-Related Pathology and Cognitive Deficits |
| title_full | Branched-Chain Amino Acids Are Linked with Alzheimer’s Disease-Related Pathology and Cognitive Deficits |
| title_fullStr | Branched-Chain Amino Acids Are Linked with Alzheimer’s Disease-Related Pathology and Cognitive Deficits |
| title_full_unstemmed | Branched-Chain Amino Acids Are Linked with Alzheimer’s Disease-Related Pathology and Cognitive Deficits |
| title_short | Branched-Chain Amino Acids Are Linked with Alzheimer’s Disease-Related Pathology and Cognitive Deficits |
| title_sort | branched chain amino acids are linked with alzheimer s disease related pathology and cognitive deficits |
| topic | glucose metabolism BCAA neurotransmitters Aβ-42 Tau 5xFAD |
| url | https://www.mdpi.com/2073-4409/11/21/3523 |
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