Cerebrovascular contributions to APOE4-mediated brain bioenergetic deficits in Alzheimer's disease

The apolipoprotein E (APOE) E4 allele is one of the major genetic risk factors for late-onset
Alzheimer’s disease (AD) and an important contributor to cerebrovascular (CV) dysfunction,
which is now considered a major component of AD pathology. Recent advances in AD research
suggest that E4 carriers have an age-dependent vulnerability in supplying glucose to the brain,
which corresponds with lower glucose metabolism and precedes brain amyloid and tau
pathologies. The CV system regulates glucose transport to the brain to support neuronal
bioenergetics. With age, individuals with the E4 allele experience deficits in their ability to
transport nutrients to the brain, which eventually, forces neurons to perform fatty acid (FA)
metabolism. Fatty acid metabolism is harmful if performed in neurons as it can contribute to
oxidative stress. The process of FA metabolism requires L-carnitine for transporting FA as
acylcarnitines (CAR) into mitochondria (L-carnitine bioenergetics). The importance of this
system in AD is highlighted by our recent study showing that L-carnitine-bioenergetic deficits are
present in E4 carriers and correlate with CV pathologies in AD. Our animal studies herein show
pathways that link glucose sensing with acetyl-CoA carboxylase (ACC) for L-carnitine-
bioenergetics are altered in the cerebrovasculature of mice with targeted replacement of mouse
APOE with human APOE4 (E4-TR) and AD mouse models with the human APOE4 isoform.
We, therefore, hypothesize that E4 disrupts L-carnitine-bioenergetics within the CV cells, which
corresponds with impaired transport of nutrients to the brain parenchyma. This increases the
reliance on L-carnitine-bioenergetics within neurons and contributes to oxidative stress and
inflammation in the brain. To test this hypothesis, we will first determine whether brain
endothelial cells (BEC) or mural cells experience altered L-carnitine bioenergetics and
determine the differential impact of APOE genotypes within both cells with age. We will then
determine if boosting L-carnitine bioenergetics pathways by inhibiting ACC in BEC will help
restore nutrient balance in the brain parenchyma. The proposed studies will provide novel
insights into the role of ACC-mediated L-carnitine bioenergetics for developing therapeutic
strategies specifically targeting E4 carriers, who experience a significantly higher
cerebrovascular disease burden associated with AD pathogenesis.

Grant Number: 1R21AG080375-01A1
NIH Institute/Center: NIH
Principal Investigator: Laila Abdullah