Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders

Dysfunction of the blood–brain barrier and other neurovascular deficits are features of several neurodegenerative disorders. In this Review, Berislav Zlokovic explores the evidence indicating that vascular-derived insults initiate and/or contribute to neuronal degeneration in these disorders, most notably in Alzheimer's disease. He also discusses the therapeutic opportunities that are related to these neurovascular deficits. The neurovascular unit (NVU) comprises brain endothelial cells, pericytes or vascular smooth muscle cells, glia and neurons. The NVU controls blood–brain barrier (BBB) permeability and cerebral blood flow, and maintains the chemical composition of the neuronal 'milieu', which is required for proper functioning of neuronal circuits. Recent evidence indicates that BBB dysfunction is associated with the accumulation of several vasculotoxic and neurotoxic molecules within brain parenchyma, a reduction in cerebral blood flow, and hypoxia. Together, these vascular-derived insults might initiate and/or contribute to neuronal degeneration. This article examines mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, and highlights therapeutic opportunities relating to these neurovascular deficits.