The role of glia and the cerebral vasculature in dementia (360G-Wellcome-219366_Z_19_Z)

The cerebral vasculature and glial cells play crucial but poorly understood roles in initiating Alzheimer’s disease (AD) and related dementias, contributing to cognitive decline via a loss of synapses and neurons. We have shown that: (i) a major reduction of cerebral blood flow occurs early in human AD because oligomeric amyloid beta (Aß) evokes constriction of brain capillaries by contractile pericytes; (ii) the blood flow reduction in AD may reflect microglia controlling pericytes; (iii) microglia-mediated phagocytosis, which removes both Aß and synapses, is regulated by ion channels and receptors; (iv) decreased blood flow and AD alter node of Ranvier length in myelinated axons, which will change axonal conduction speed and thus neural circuit function. Now, focusing on Aß and decreased blood flow, we will investigate how vascular and glial function contribute to dementia, by: (A) defining the mechanisms underlying Aß-evoked capillary constriction, and developing therapeutic approaches to restoring blood flow; (B) characterising how microglia and astrocytes remove Aß and synapses, and investigating how to control this; (C) studying how Aß and decreased blood flow damage myelin and nodes of Ranvier, and how to prevent this. Together, this work will identify novel non-neuronal therapeutic targets for treating dementia.