Alzheimer's Disease: The Link Between Amyloid-β and Neurovascular Dysfunction

Abstract

While prevailing evidence supports that the amyloid cascade hypothesis is a key component of Alzheimer's disease (AD) pathology, many recent studies indicate that the vascular system is also a major contributor to disease progression. Vascular dysfunction and reduced cerebral blood flow (CBF) occur prior to the accumulation and aggregation of amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Although research has predominantly focused on the cellular processes involved with Aβ-mediated neurodegeneration, effects of Aβ on CBF and neurovascular coupling are becoming more evident. This review will describe AD vascular disturbances as they relate to Aβ, including chronic cerebral hypoperfusion, hypertension, altered neurovascular coupling, and deterioration of the blood-brain barrier. In addition, we will describe recent findings about the relationship between these vascular defects and Aβ accumulation with emphasis on in vivo studies utilizing rodent AD models.

Keywords: Amyloid-β peptide; amyloid cascade hypothesis; blood-brain barrier; cerebral amyloid angiopathy; chronic cerebral hypoperfusion; functional hyperemia; in vivo mouse model; in vivo rat model; neurovascular coupling; vascular hypothesis.

Fig. 1.

Neurovascular deficits linked to Alzheimer’s disease. The illustration shows the various cell types involved in regulating localized cerebral blood flow along an arteriole bifurcating into capillaries. Neurovascular deficits related to AD include (1) chronic cerebral hypoperfusion (CCH), a reduction in blood flow into the brain that occurs prior to symptomology, (2) neurovascular coupling (NVC) deficits, and (3) blood-brain barrier (BBB) disruption that can be related to (4) cerebral amyloid angiopathy (CAA), characterized by the deposition of Aβ in blood vessels. Image created with BioRender.com.

Fig. 2.

Vascular Theory of Alzheimer’s disease. Hypertension and other vascular risk factors contribute to the likelihood of cerebral blood vessels damage and microinfarcts. This causes blood-brain barrier (BBB) deterioration and diminishes blood supply to the affected cerebral regions. As the BBB breaks down, cells involved in neurovascular coupling are affected and consequently, are not able to properly regulate and supply local cerebral blood flow (CBF). Concurrently, the abnormal accumulation of amyloid-β (Aβ) in the brain parenchyma and in cerebral blood vessels contributes to the local CBF deficits. Whereas soluble Aβ can decrease CBF by directly constricting blood vessels, Aβ deposition is known to contribute to CBF reduction or chronic cerebral hypoperfusion. Over time, essential macromolecules to support neuronal network activity becomes limited leading to oxidative, neuronal and glial cell damage, and eventual neurodegeneration. Image created with BioRender.com.