Vascular Dysfunction in Alzheimer’s Disease: A Prelude to the Pathological Process or a Consequence of It?

Abstract

Alzheimer’s disease (AD) is the most prevalent form of dementia. Despite decades of research following several theoretical and clinical lines, all existing treatments for the disorder are purely symptomatic. AD research has traditionally been focused on neuronal and glial dysfunction. Although there is a wealth of evidence pointing to a significant vascular component in the disease, this angle has been relatively poorly explored. In this review, we consider the various aspects of vascular dysfunction in AD, which has a significant impact on brain metabolism and homeostasis and the clearance of β-amyloid and other toxic metabolites. This may potentially precede the onset of the hallmark pathophysiological and cognitive symptoms of the disease. Pathological changes in vessel haemodynamics, angiogenesis, vascular cell function, vascular coverage, blood-brain barrier permeability and immune cell migration may be related to amyloid toxicity, oxidative stress and apolipoprotein E (APOE) genotype. These vascular deficits may in turn contribute to parenchymal amyloid deposition, neurotoxicity, glial activation and metabolic dysfunction in multiple cell types. A vicious feedback cycle ensues, with progressively worsening neuronal and vascular pathology through the course of the disease. Thus, a better appreciation for the importance of vascular dysfunction in AD may open new avenues for research and therapy.

Alterations in resting-state network dynamics along the Alzheimer’s disease continuum: a combined MEG-PET/MR approach

“…However, vascular changes (e.g., in vessel hemodynamics, angiogenesis, vascular cell function as well as blood-brain barrier permeability; for a review, see 33 ) are an early preclinical feature of AD pathology leading to modifications in cortical blood flow even before the onset of clinical symptoms 34 . Thus, it cannot be ruled out that parts of rsfMRI changes observed along the AD continuum actually reflect vascular rather than neuronal changes per se.…”

Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signalling

“…Studies examining human brain microvessel density in the context of "normal" ageing have revealed inconsistent results (increased/decreased/no change) in aged vs. young individuals depending on brain region and microvessel type studied [39][40][41][42] . Despite widespread interest in vascular pathology in AD, there is also debate as to the relative roles of pro-and anti-angiogenic processes during disease progression 1 . For example, whilst some studies demonstrate increased angiogenesis in post mortem human AD or huAPP-mouse brain 3,5,6,43 , others report endothelial cell apoptosis and loss of vasculature 33,44 .…”

“…For example, whilst some studies demonstrate increased angiogenesis in post mortem human AD or huAPP-mouse brain 3,5,6,43 , others report endothelial cell apoptosis and loss of vasculature 33,44 . It seems likely that such studies represent different stages of disease, with initial increases in angiogenesis (potentially as a result of rising Aβ that occurs in ageing 45,46 ) being overtaken by cell death in the end stages 1 . Clearly, more work is required to fully understand the complex relationships between age, AD and vascular pathology, although our work indicates pathological angiogenesis can be induced by dysregulated Aβ processing even in the absence of ageing.…”

“…Alzheimer's disease (AD) is closely associated with alterations in the vascular system 1 . Multiple studies in humans and animal models have described pathological vascular changes in AD 2 , including disruption to the neurovascular unit 3 and blood-brain barrier 4 , increased microvessel density 3,5,6 , arteriolar and venular tortuosity 7,8 and vascular Aβ accumulation 9 .…”

Investigating protein thiol chemistry associated with dehydroascorbate, homocysteine and glutathione using mass spectrometry

“…The formation of reactive oxygen species (ROS) is a general consequence of metabolism and adaptation to an environment with oxygen. Increased or deregulated formation of ROS resulting in oxidative stress may play a significant role in numerous ailments spanning inflammation to ageing, cancer and cardiovascular and neurodegenerative diseases 1–3 . Deregulated oxidative stress may cause functional degeneration of macromolecules including lipids, proteins and nucleic acids, which ultimately leads to autophagocytosis or cell death 4,5 …”