Abstract
Introduction: Sporadic Alzheimer's disease (AD) is strongly correlated with impaired brain glucose metabolism, which may affect AD onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain. Methods: RNA-seq profiles of post mortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer's Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, neurons, oligodendrocytes. Results: In oligodendrocytes, both glycolytic and ketolytic pathways were significantly impaired in AD brains. Ketolytic gene expression was not significantly altered in neurons, astrocytes, and microglia. Discussion: Oligodendrocytes may contribute to brain hypometabolism observed in AD. These results are suggestive of a potential link between hypometabolism and dysmyelination in disease physiology. Additionally, ketones may be therapeutic in AD due to their ability to fuel neurons despite impaired glycolytic metabolism.
| Original language | English |
|---|---|
| Pages (from-to) | 1474-1486 |
| Number of pages | 13 |
| Journal | Alzheimer's and Dementia |
| Volume | 17 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 2021 |
Bibliographical note
Publisher Copyright:© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association
Funding
We recognize the contributions of Brigham Young University, including the Office of Research Computing, for supporting our research. This work was supported by the following grants from the National Institutes of Health: RF1AG054052 (JK), R01AG044546 (CC), P01AG003991 (CC), RF1AG053303 (CC), RF1AG058501 (CC), U01AG058922 (CC), and R01AG057777 (OH). This work was also supported by the BrightFocus Foundation grant A2020118F (JM). Study data were provided by the following sources: The Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr. Nilufer Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL, using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by National Institute on Aging grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949; NINDS grant R01 NS080820; CurePSP Foundation; and support from Mayo Foundation. Study data includes samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research. BTB receives royalties from the sale of a book about insulin resistance. We recognize the contributions of Brigham Young University, including the Office of Research Computing, for supporting our research. This work was supported by the following grants from the National Institutes of Health: RF1AG054052 (JK), R01AG044546 (CC), P01AG003991 (CC), RF1AG053303 (CC), RF1AG058501 (CC), U01AG058922 (CC), and R01AG057777 (OH). This work was also supported by the BrightFocus Foundation grant A2020118F (JM). Study data were provided by the following sources: The Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr. Nilufer Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL, using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by National Institute on Aging grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949; NINDS grant R01 NS080820; CurePSP Foundation; and support from Mayo Foundation. Study data includes samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05‐901 and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research. BTB receives royalties from the sale of a book about insulin resistance.
| Funders | Funder number |
|---|---|
| Arizona Alzheimer's Research Center | |
| CurePSP Foundation | |
| Mayo Clinic Alzheimer's Disease Research Center | |
| National Institutes of Health (NIH) | U01AG058922, RF1AG058501, RF1AG054052, R01AG044546, P01AG003991, RF1AG053303 |
| National Institute on Aging | P50 AG016574, R01 AG017216, U01 AG006786, U01 AG006576, R01 AG025711, U01 AG046139, R01 AG018023, R01AG057777, R01 AG003949, R01 AG032990 |
| Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | U24 NS072026, P30 AG19610, R01 NS080820 |
| The Michael J Fox Foundation for Parkinson's Research | |
| Mayo Clinic Rochester | |
| BrightFocus Foundation | A2020118F |
| Mayo Foundation for Medical Education and Research | |
| Arizona Department of Health Services | 211002 |
| Arizona Biomedical Research Commission | 4001, 0011, 1001, 05‐901 |
Keywords
- Alzheimer's disease
- astrocytes
- glycolysis
- ketolysis
- metabolic RNA-seq profiles
- microglia
- neurons
- oligodendrocytes
ASJC Scopus subject areas
- Epidemiology
- Health Policy
- Developmental Neuroscience
- Clinical Neurology
- Geriatrics and Gerontology
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
