Evidence of endothelial dysfunction in the development of Alzheimer's disease: Is Alzheimer's a vascular disorder?

Abstract

The etiology of Alzheimer's disease (AD) remains unclear. The emerging view is that cerebrovascular dysfunction is a feature not only of cerebrovascular diseases, such as stroke, but also of neurodegenerative conditions, such as AD. In AD, there is impaired structure and function of cerebral blood vessels and cells in the neurovascular unit. These effects are mediated by vascular oxidative stress. Injury to the neurovascular unit alters cerebral blood flow regulation, depletes vascular reserves, disrupts the blood-brain barrier and reduces the brain's repair capacity. Such injury can exacerbate the cognitive dysfunction exerted by incident ischemia and coexisting neurodegeneration. This article summarises data regarding cardiovascular risk factors, vascular abnormalities and brain endothelial damage in AD. In view of accumulating evidence of vascular pathology in AD, we also review the literature (MEDLINE, EMBASE) for clinical evidence of impaired endothelial function in AD. A total of 15 articles investigating endothelial dysfunction in AD were identified. 10 of these articles showed impaired endothelial function in AD patients. The current literature suggests endothelial dysfunction may be involved in the pathogenesis of AD. This aspect of AD pathology is particularly interesting in view of its potential for therapeutic intervention. Future research on endothelial function in AD should concentrate on population-based analysis and combine multiple methods to evaluate endothelial function.

Keywords: Alzheimer’s; dementia; endothelial dysfunction; endothelium; etiology; neurodegeneration; pathology; vascular disease.

Figures

Figure 1

The neurovascular unit. This diagram depicts a cerebral blood vessel and surrounding brain parenchyma that comprise the neurovascular unit. The neurovascular unit encompasses cell-cell and cell-matrix interactions between component endothelial, glial, and neuronal cells. (Image adapted with permission from Iadecola 2004) [268].

Figure 2

Overview of the vascular and amyloid hypotheses of Alzheimer’s disease. The amyloid hypothesis proposes that overexpression of amyloid precursor protein (APP) is the primary cause of Alzheimer’s disease (AD). Mutations in the presenilin 1, presenilin 2 and APP gene increase amyloid deposition and raise the risk of developing AD. Senile plaques are a key pathological feature of AD and in mouse models plaque formation is associated with neuronal damage. The vascular hypothesis suggests vascular dysfunction associated with ageing is the primary trigger of AD. The prevalence of vascular risk factors is greater in the elderly population and vascular disease is strongly associated with risk of AD. Cerebral hypoperfusion resulting from impaired vasoregulation in vascular disorders causes a neuroglial energy crisis resulting in cognitive. Vascular dysfunction promotes the conversion from mild cognitive impairment to AD.

Figure 3

Interaction between vascular disease and AD pathology. Arrows indicate how cerebrovascular factors influence amyloid processing. Hypoxia resulting from vascular disease (e.g atherosclerosis) causes increased expression of hypoxia-inducible factor (HIF)-1α. HIF-1α binds to the hypoxia-responsive element on amyloid cleaving enzyme BACE1. The resulting upregulation of BACE1 mRNA expression increases the production of Aβ fragments. Hypoperfusion resulting from vascular disease and old age further increases BACE1 activity. In addition, hypoperfusion may contribute to oxygen deficiency and cause a neuroglial energy crisis, further ameliorating amyloid plaque production, CAA and ischaemia. CAA = Cerebral amyloid angiopathy, BACE1 = beta secretase 1, sAPP = secreted form of beta-APP, APP = amyloid precursor protein, Aβ = beta amyloid peptide. Image adapted with permission from Kalaria et al. [59].

Figure 4

Proposed synergistic relationship between vascular insufficiency and Alzheimer’s disease (Iadecola, 2010 [269]). Vascular insufficiency resulting from vascular risk factors (e.g vascular dementia) can promote β-amyloid (Aβ) production by increasing amyloid cleaving enzyme β secretase-1 and reducing Aβ clearance. Overexpression of amyloid precursor protein in Alzheimer’s disease leads to the formation of senile Aβ plaques, which may induce ROS-mediated vascular damage and compromised vasoregulation. Thus, vascular insufficiency and β-amyloid production may interact via a positive feedback mechanism exacerbating cognitive decline and increasing the risk of dementia.

Figure 5

Membrane-related amyloid fibrillogenesis and oxidative stress in the pathogenesis of Alzheimer’s disease. Ageing is associated with reduced tissue antioxidant levels, oxidative lipid damage and enhanced Aβ protein aggregation. These changes are even more pronounced in Alzheimer’s disease. Thiol-mediated antioxidant activity is absent in Apolipoprotein E4 alleles which may allow excess oxidative damage to the lipids in lipoprotein particles. Aβ proteins have a pro-oxidant activity towards the polyunsaturated lipids of cell membranes. Lipid oxidation products may exert direct neurotoxicity or induce structural changes in the His residues of Aβ42, enhancing its membrane affinity. Furthermore, these products may facilitate the oligomerization of Aβ40 and promote fibrillogenesis. Highly reactive oxygen species may be produced as a result of trauma induced-inflammation or fibrillogenesis. Inflammation may also occur in the presence of vascular disease (e.g atherosclerosis). During these processes, Aβ may form neurotoxic pores or channels in endothelial or neuronal membranes. Image adapted from Axelsen et al. [270].