Astrocyte Calcium Rescue to Overcome Familial Alzheimer’s vascular Dysfunction (ACROFAD)

Among the pathological signs commonly found in the brain of Alzheimer’s disease patients, besides amyloid plaques and neurofibrillary tangles, are several indicators of vascular pathology. Decrease of cerebral vascularization, enlarged perivascular space, alterations of the blood brain barrier can worsen AD progression, increasing neuroinflammation and neuronal loss, and shifting the threshold for dementia in both familial and sporadic AD patients. Reducing the risk and the effects of vascular pathology appears thus as a realistic therapeutic strategy to dampen AD progression.

In this project, we will face vascular dysfunction by acting on astrocytes, glial cells exerting a fundamental homeostatic and protective role in the brain. Astrocyte processes surround cerebral vasculature as central components of the gliovascular unit, which controls the regulation of blood flow, the integrity of blood brain barrier, the transport of nutrients and the clearance of toxic species (e.g. amyloid). Moreover, astrocytes actively support and modulate neuronal function and plasticity.

At the basis of astrocyte activity stands their intracellular signalling system based on cytosolic Ca²⁺ elevations. We recently revealed a reduction in such signals linked to memory loss in a mouse model of familial AD with mutations associated to cerebrovascular pathology in familial AD patients. Notably, we developed a genetic rescue strategy that fully recovers both astrocyte Ca²⁺ signals and neuronal plasticity. In this project, we will characterize vascular dysfunction in the familial AD model and apply our rescue strategy to assess its potential to restore astrocyte homeostatic role in cerebrovascular physiology and ultimately dampen AD progression.