Dysfunction of the Regulation of Cerebral Blood Flow in Alzheimer Disease

The goal of my project is to investigate how ApoE4, a major genetic risk factor for Alzheimer disease, induces a dysfunction of the regulation of blood flow in the brain.

Accumulating evidence suggest that early alteration in the blood flow in the brain is an important contributing factor to Alzheimer’s disease (AD). Individuals with apolipoprotein E e4 (ApoE4), a leading genetic risk factor for AD, have reduced blood flow to the brain; however, the underlying mechanisms are unknown. Therefore, the aim of this project is to study the brain blood flow dysfunction caused by ApoE4 with the ultimate goal of identifying new pathways that could be used to develop new drugs for the prevention and treatment of dementia.

The concept that perivascular macrophages could be both the source and target of ApoE4 around penetrating blood vessels support the idea of a potential and previously unrecognized cell-autonomous pathogenic role of brain resident macrophages. Furthermore, we will use a novel mouse (Mrc1CreERT2) to conditionally target perivascular macrophages, allowing us to test our hypotheses with a cellular specificity not previously attainable.

The proposed study will fill a knowledge gap. We already know that neurovascular dysfunction contributes to the development of Alzheimer disease, but the cellular and molecular mechanisms responsible are still unknown. The proposed experiments will identify these cellular and molecular mechanisms and raise the possibility that perivascular macrophages could be therapeutic targets to counteract the neurovascular dysfunction observed in individuals with the ApoE4 genotype.