Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most common form of age-related dementia. Despite decades of research, the etiology and pathogenesis of AD are not well understood. Brain glucose hypometabolism has long been recognized as a prominent anomaly that occurs in the preclinical stage of AD. Recent studies suggest that glycolytic metabolism, the cytoplasmic pathway of the breakdown of glucose, may play a critical role in the development of AD. Glycolysis is essential for a variety of neural activities in the brain, including energy production, synaptic transmission, and redox homeostasis. Decreased glycolytic flux has been shown to correlate with the severity of amyloid and tau pathology in both preclinical and clinical AD patients. Moreover, increased glucose accumulation found in the brains of AD patients supports the hypothesis that glycolytic deficit may be a contributor to the development of this phenotype. Brain hyperglycemia also provides a plausible explanation for the well-documented link between AD and diabetes. Humans possess three primary variants of the apolipoprotein E (ApoE) gene – ApoE∗ϵ2, ApoE∗ϵ3, and ApoE∗ϵ4 – that confer differential susceptibility to AD. Recent findings indicate that neuronal glycolysis is significantly affected by human ApoE isoforms and glycolytic robustness may serve as a major mechanism that renders an ApoE2-bearing brain more resistant against the neurodegenerative risks for AD. In addition to AD, glycolytic dysfunction has been observed in other neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, strengthening the concept of glycolytic dysfunction as a common pathway leading to neurodegeneration. Taken together, these advances highlight a promising translational opportunity that involves targeting glycolysis to bolster brain metabolic resilience and by such to alter the course of brain aging or disease development to prevent or reduce the risks for not only AD but also other neurodegenerative diseases.

Validating a Genomic Convergence and Network Analysis Approach Using Association Analysis of Identified Candidate Genes in Alzheimer’s Disease

“…In fact, in vitro experiment that generated insulin-secreting beta cells from human pluripotent stem cells has shown the fundamental role of actin in pancreatic progenitor gene expression and endocrine function ( Hogrebe et al, 2020 ; Siehler et al, 2020 ). The pancreas has a central role in the glucose metabolism, and the glycolytic dysfunction has been associated with the dysfunction of Alzheimer’s brains, such as synaptic impairment, brain atrophy, mitochondrial impairment, and Aβ deposition ( Zhang et al, 2021 ). Moreover, diabetes has been classified as a risk factor for AD ( Profenno et al, 2010 ), especially when associated with the APOE ε4 genotype.…”

Vitamin B12 impacts amyloid beta-induced proteotoxicity by regulating the methionine/S-adenosylmethionine cycle

“…Both Aβ oligomers and oxidative stress can induce membrane damage, which leads to ion leakage and necessitates increased ATP expenditure by ATPases to maintain ionic gradients and membrane potential ( Butterfield and Halliwell, 2019 ; Ronquist and Waldenström, 2003 ; Yang et al, 2017 ). Glycolysis is the dominant ATP production pathway used to fuel plasma membrane ATPases ( Ronquist and Waldenström, 2003 ; Yellen, 2018 ), and studies suggest a link between impaired glucose metabolism and the severity of neurodegenerative diseases ( An et al, 2018 ; Zhang et al, 2021 ). We found that dietary vitamin B 12 reduced energy crisis and was protective in C. elegans models of AD, Huntington’s disease, and ALS.…”

Disruption of Glucose Metabolism in Aged Octodon degus: A Sporadic Model of Alzheimer's Disease

“…Cerebral glucose hypometabolism has been used as an early-stage biomarker prior to the onset of clinical symptoms in patients with AD (Mosconi et al, 2008a ; Bulleid, 2012 ; Johnson et al, 2020 ; Lu et al, 2020 ; Tams et al, 2021 ; Zhang et al, 2021 ). Notably, the stimulation of brain glucose uptake is able to delay AD pathological decline and results in an improvement in cognitive tests, further reinforcing the idea that glucose metabolism in the brain is a fundamental process that is altered in patients with AD (Winkler et al, 2015 ; Gejl et al, 2017 ; Lee et al, 2019 ; Minhas et al, 2021 ).…”