Monday, May 12, 2025
5/12/2025
Targeting the astrocyte-cerebrovasculature system to correct brain bioenergetics defects associated with APOE4 - The Apolipoprotein E4 (APOE4) allele is the major genetic risk factor for Alzheimer's disease (AD), a neurodegenerative condition marked by impairment of the brain bioenergetics. Energy dynamics in the brain are tightly linked to neuronal activity and have a major impact on neuronal function. Glucose is the main source of energy for the brain, and its cerebral fueling is guaranteed by glucose transporters within the brain vascular system. Glucose is directly consumed by neurons or can be metabolized by astrocytes into lactate, which is then exported to neurons as a supplementary energy source. When glucose supply to the brain from the blood is insufficient, astrocytes can also generate fatty acid (FA) metabolites through mitochondrial fatty acid (FA) β- oxidation (FAO) and these metabolites serve as alternative energy substrates for neurons. APOE4-mediated disturbances of the FAO have been observed in cells at the blood brain barrier (BBB) and associated with alterations in the BBB integrity suggesting that perturbations of the energy metabolism of these cells could lead to deficits of neuronal energy supply in E4 carriers. Our previous work showed the AMP-activated protein kinase (AMPK)-mediated acetyl-CoA carboxylase activation is affected in the cerebrovasculature of APOE4-TR and E4FAD mice, with changes more pronounced in the presence of AD pathology in EFAD mice. As this system plays a key role in linking glucose uptake and metabolism with FAO, we hypothesize that brain bioenergetics deficits in E4 carriers, and more importantly in the presence of AD-related insults, result from a combination of low glucose availability due to its poor transit across the BBB, particularly through the cerebrovasculature (CV), and their reduced ability to switch towards compensatory mechanisms to meet brain bioenergetic needs. This could be mediated by an inhibition of the GLP-1R-AMPK-ACC pathway in the E4-CV/astrocyte crosstalk system, which would lower the FAO in these cells and alter their capacity to maintain brain bioenergetic homeostasis. Targeting the GLP-1R-AMPK-ACC pathway in E4 CV/astrocytes could serve as a promoter of the FAO to correct the bioenergetics imbalance in E4 carriers. However, the impact of modulating this pathway in the CV and astrocytes has not yet been fully investigated. Hence, using an AD mouse model, we will examine the influence of different APOE genotypes on the GLP-1R-AMPK-ACC pathway in CV and astrocytes. We will also determine whether treatments that induce activation of the GLP-1R-AMPK-ACC pathway could regulate FAO in E4 carriers, which could open the door to new ways of treating AD. Thus, these proposed studies will provide critical insight into the development of approaches for targeting brain bioenergetic pathways to prevent or reduce cognitive decline in AD among high-risk APOE E4 carriers.
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