Pathological changes within the cerebral vasculature in Alzheimer’s disease: New perspectives

Abstract

Cerebrovascular disease underpins vascular dementia (VaD), but structural and functional changes to the cerebral vasculature contribute to disease pathology and cognitive decline in Alzheimer's disease (AD). In this review, we discuss the contribution of cerebral amyloid angiopathy and non-amyloid small vessel disease in AD, and the accompanying changes to the density, maintenance and remodelling of vessels (including alterations to the composition and function of the cerebrovascular basement membrane). We consider how abnormalities of the constituent cells of the neurovascular unit -particularly of endothelial cells and pericytes -and impairment of the blood-brain barrier (BBB) impact on the pathogenesis of AD. We also discuss how changes to the cerebral vasculature are likely to impair Aβ clearance -both intra-periarteriolar drainage (IPAD) and transport of Aβ peptides across the BBB, and how impaired neurovascular coupling and reduced blood flow in relation to metabolic demand increase amyloidogenic processing of APP and the production of Aβ. We review the vasoactive properties of Aβ peptides themselves, and the probable bi-directional relationship between vascular dysfunction and Aβ accumulation in AD. Lastly, we discuss recent methodological advances in transcriptomics and imaging that have provided novel insights into vascular changes in AD, and recent advances in assessment of the retina that allow in vivo detection of vascular changes in the early stages of AD. K E Y W O R D SAlzheimer's disease, blood-brain barrier, cerebral blood flow, neurovascular coupling, pericyte, vasculature How to cite this article: Fisher RA, Miners JS, Love S. Pathological changes within the cerebral vasculature in Alzheimer's disease: New perspectives.

Monocyte-derived cells invade brain parenchyma and amyloid plaques in human Alzheimer’s disease hippocampus

“…Thus, vascular endothelial activation, associated with AD or other pathologies, may be responsible for the recruitment and infiltration of inflammatory cells into the cerebral parenchyma. These data are consistent with the diminished integrity of the BBB and endothelial activation associated with cerebral amyloid angiopathy, vascular dementia, and AD [14,39,54] Furthermore, we have also recently reported the existence of microglial degeneration in specific areas (dentate gyrus) of approximately 50% of AD samples [51]. Since microglial depopulation also induces monocyte infiltration [9], microglial degeneration could also be a pathological factor that induces higher monocyte infiltration.…”

“…A focus map, created by selecting multiple coordinates with the optimal Z position, was automatically generated across the entirety section using a software-based autofocus function in the color brightfield mode. Quality parameters were not modified at any step staying uniform in all samples: gain (white balance) R:1.87; G1.00; B1.78; brightness 0.00, contrast 1.00, gamma 1.00, sharpness 6.00, and saturation 0.00)The high quality virtual slides were viewed using the Olyvia 2.6 software (Olympus, Denmark) and images from the region of interest were extracted (10)(11)(12)(13)(14)(15) images/section; image size of 1879 × 872 pixels; pixel size = 72ppp). Quantitative analyses were performed using the Visilog 6.3 image analysis software (Noesis, France).…”

“…It is the most common pathologic cause of dementia in the late adult life, and no cure is currently available. AD is neuropathologically characterized by abnormal aggregation of the amyloid-β (Abeta) peptides in plaques and hyperphosphorylated neuronal tau protein in neurofibrillary tangles, synaptic damage, and neuronal loss, together with glial-mediated innate immune responses [ 14 ].…”

The characteristics of arterial spin labeling cerebral blood flow in patients with subjective cognitive decline: The Chinese imaging, biomarkers, and lifestyle study

“…Vascular dysfunction result in reduced clearance of Aβ by periarteriolar and impaired Aβ transporters across the blood-brain barrier, which can increase Aβ deposition. Aβ induces contraction of pericytes and vascular smooth muscle cells and then exacerbates hypoperfusion ( Fisher et al, 2022 ). Duan et al (2020) have proposed that CBF could be a neuroimaging marker to reflect the degree of cognitive impairment.…”

Reconsidering the role of blood-brain barrier in Alzheimer’s disease: From delivery to target

“…Aβ as well as its lipid carrier ApoE (encoded by the homonymous susceptibility gene) are vasculopathic, proinflammatory, impair Aβ degradation by microglial cells and astrocytes, impede efficient clearance and induce a degeneration of endothelial cells which is independent of other conditions ( Kurz et al, 2021 ). Aβ peptides trigger vasoactivity activating pericytes and vascular smooth muscle cells further impairing BBB function ( Fisher et al, 2022 ). For example, in a rodent model of AD, reactive oxygen species trigger the release of endothelin-1 that elicits pericyte contraction by acting on endothelin-A receptors, thus causing capillary constriction and reducing cerebral blood flow.…”