Pathogenic Angiogenic Mechanisms in Alzheimer's Disease

Abstract

Vascular dysfunction is a crucial pathological hallmark of Alzheimer's disease (AD). Studies have reported that beta amyloid (Aβ) causes increased blood vessel growth in the brains of AD mouse models, a phenomenon that is also seen in AD patients. This has given way to an alternative angiogenesis hypothesis according to which, increased leakiness in the blood vessels disrupts the blood-brain barrier (BBB) and allows unwanted blood products to enter the brain causing progression of disease pathology, promoting amyloid clumping and aggregation along with impaired cerebral blood flow. Furthermore, the expression of melanotransferrin in AD model and patients may contribute to angiogenesis. The objective of this chapter is to attempt to establish a link between the vascular damage and AD pathology. Curbing the vascular changes and resulting damage seen in the brains of AD model mice and improving their cognition by treating with FDA-approved anti-angiogenic drugs may expedite the translational potential of this research into clinical trials in human patients. This direction into targeting angiogenesis will facilitate new preventive and therapeutic interventions for AD and related vascular diseases.

Microarray analysis of verbenalin-treated human amniotic epithelial cells reveals therapeutic potential for Alzheimer’s Disease

“…Although it is not clear yet how Aβ aggregation affects NRG1 expression in the AD brain, it is evident that NRG1 has therapeutic potential for AD by inducing neurogenesis, improving cognitive deficits, and restoring synaptic plasticity with [61] or without [63] affecting Aβ level. The angiogenic factor VEGF is implicated in pathological angiogenesis in the AD brain [39,40]; however, it is reported that Aβ antagonizes VEGF activity both in vitro and in vivo in a transgenic mouse model of AD [62]. The exogenous addition of VEGF can partially rescue the anti-angiogenic effect of Aβ peptides in vitro [62].…”

“…Postmortem studies on human brains found evidence of increased angiogenesis in the hippocampus, mid-frontal cortex, and other parts of AD brains compared to healthy individuals [38]. The amalgamation of accumulated Aβ and neuroinflammation causes diminished blood perfusion of the brain, leading to hypoperfusion/hypoxia-induced angiogenesis through the upregulation of several proangiogenic factors, particularly VEGF [39,40].…”

Imaging blood–brain barrier disruption in neuroinflammation and Alzheimer’s disease

“…Accumulation of Aβ and tau aggregates accelerates BBB pathologies by promoting aberrant angiogenesis via VEGF dysregulation and cerebral amyloid angiopathy (Biron et al, 2011;Zlokovic, 2011;Singh et al, 2017;Steinman et al, 2021). Furthermore, Aβ aggregates promote microglia activation and inflammatory cytokine expression including IL-1β and TNF, which recruit leukocytes to the brain parenchyma, further intensifying BBB breakdown and vessel leakage (Hussain et al, 2021).…”

Reversing pathology in a preclinical model of Alzheimer's disease by hacking cerebrovascular neoangiogenesis with advanced cancer therapeutics

“…Growing evidence supports the concept that, in addition to neurons themselves, the neurovascular unit is altered in AD [7À13] and that the disease may be mediated by vascular pathogenesis [7,14,15]. Vascular risk factors and neurovascular dysfunction associated with hypotension, hypertension, cholesterol levels, type II diabetes mellitus, smoking, oxidative stress and iron overload, including the risk factor Apolipoprotein E epsilon 4 allele (APOEe4), are increasingly found to play integral roles in the pathogenesis of stroke and AD [11,15,16]. Notably, cerebrovascular amyloid angiopathy (CAA) is present in the majority of AD cases [16] and is characterized by the presence of Ab in the pial and intracerebral small arteries and capillaries [17,18], and is associated with microaneurysms and dementia [19].…”

“…Vascular dysfunction is gaining acceptance as a crucial pathological hallmark underlying AD pathogenesis [7,11,14,15,25,26] however, the mechanism underpinning these observations has only begun to be illuminated. Studies in AD mouse models [22,23] and in postmortem studies on human brain tissues [24] indicate that pathogenic cerebrovascular neoangiogenesis and blood-brain barrier (BBB) tight junction disruption and vessel leakage appear to occur as a compensatory response to impaired CBF [20,21,28].…”