Abstract
Insurmountable evidence has demonstrated a strong association between Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), along with various other cerebrovascular diseases. One form of CAA, which is the accumulation of amyloid-beta peptides (Aβ) along cerebral vessel walls, impairs perivascular drainage pathways and contributes to cerebrovascular dysfunction in AD. To date, CAA research has been primarily focused on arterial Aβ, while the accumulation of Aβ in veins and venules were to a lesser extent. In this review, we describe preclinical models and clinical studies supporting the presence of venular amyloid and potential downstream pathological mechanisms that affect the cerebrovasculature in AD. Venous collagenosis, impaired cerebrovascular pulsatility, and enlarged perivascular spaces are exacerbated by venular amyloid and increase Aβ deposition, potentially through impaired perivascular clearance. Gaining a comprehensive understanding of the mechanisms involved in venular Aβ deposition and associated pathologies will give insight to how CAA contributes to AD and its association with AD-related cerebrovascular disease. Lastly, we suggest that special consideration should be made to develop Aβ-targeted therapeutics that remove vascular amyloid and address cerebrovascular dysfunction in AD.
Highlights
We propose that Aβ deposition in the venular system acts in a positive feedback manner, similar to arterial cerebral amyloid angiopathy (CAA), to increase vascular Aβ deposition from impaired interstitial fluid (ISF) efflux, and impair the cerebrovascular network
In combination with the results described by Moody and colleagues, these data indicate that venous collagenosis is enhanced by both age and Alzheimer’s disease (AD)-related pathology, such as white matter hyperintensities, and can impair cerebrovascular structure, cause venous insufficiency, increase fluid leakage/vasogenic edema, and occlude blood flow [30,46,47,52,54,55,75,76,77]
It is possible that glymphatic clearance of cerebral spinal fluid (CSF)-ISF along veins allows soluble Aβ to deposit in perivascular spaces and venular walls, similar to what is proposed for arterial CAA
Summary
Memory impairment, and loss of activities of daily living are a few of the debilitating clinical symptoms of Alzheimer’s disease (AD), the most common form of dementia [1,2]. Aβ aggregates in the form of amyloid plaques within the brain parenchyma, typically spreading through the cortex and eventually to the hippocampus [1,9], leading to synaptic loss, neuronal cell death, and brain atrophy [10,11] This neurodegenerative process contributes to the dementia that is seen in AD patients [12,13,14]. Cerebrovascular morphological alterations, blood–brain barrier (BBB) dysfunction, reduced cerebral blood flow, and decreased vascular reactivity are involved in AD [10,17,18] Another pathological hallmark of AD that contributes to vascular dysregulation is the presence of Aβ deposition in the walls of cerebral vessels, known as cerebral amyloid angiopathy (CAA) [2]. It is of significant importance to understand the role of the vasculature in AD, as well as elucidate how CAA contributes to disease progression
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