Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013;33 Suppl 1(0 1):S87-100.
doi: 10.3233/JAD-2012-129037.

Neurovascular defects and faulty amyloid-β vascular clearance in Alzheimer's disease

Abhay P Sagare  1 , Robert D Bell, Berislav V Zlokovic
Affiliations
Review

Neurovascular defects and faulty amyloid-β vascular clearance in Alzheimer's disease

Abhay P Sagare et al. J Alzheimers Dis. 2013.

Abstract

The evidence that neurovascular dysfunction is an integral part of Alzheimer's disease (AD) pathogenesis has continued to emerge in the last decade. Changes in the brain vasculature have been shown to contribute to the onset and progression of the pathological processes associated with AD, such as microvascular reductions, blood brain barrier (BBB) breakdown, and faulty clearance of amyloid β-peptide (Aβ) from the brain. Herein, we review the role of the neurovascular unit and molecular mechanisms in cerebral vascular cells behind the pathogenesis of AD. In particular, we focus on molecular pathways within cerebral vascular cells and the systemic circulation that contribute to BBB dysfunction, brain hypoperfusion, and impaired clearance of Aβ from the brain. We aim to provide a summary of recent research findings implicated in neurovascular defects and faulty Aβ vascular clearance contributing to AD pathogenesis.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Altered expression of vascular-specific genes in AD results in neurovascular dysfunction
Hypoxia downregulates mesenchyme homeobox gene-2 (MEOX2) in brain endothelial cells (BEC) (Left). Reduced levels of MEOX2 lead to unsuccessful vascular remodeling and vascular regression resulting in a primary endothelial hypoplasia and brain hypoperfusion. On the other hand, reduced levels of MEOX2 stimulate proteosomal degradation of LRP1, a major Aβ clearance receptor, leading to a loss of LRP1 from BEC and reduced Aβ clearance from brain. Hypoxia increases expression of myocardin (MYOCD) in vascular smooth muscle cells (VSMCs) resulting in elevated levels of MYOCD and serum response factor (SRF) (Right). Elevated SRF/MYOCD levels lead to increased expression of several contractile proteins and calcium-regulated channels in VSMCs resulting in a hypercontractile phenotype of small cerebral arteries and brain hypoperfusion. On the other hand, increased SRF/MYOCD activity stimulates directed expression of the sterol binding protein-2 which is a major transcriptional suppressor of LRP1. Loss of LRP1 from VSMCs diminishes Aβ clearance from small cerebral arteries leading to deposition of Aβ and amyloid in the arterial wall known as CAA, cerebral amyloid angiopathy. Changes in the expression of vascular-restricted genes MEOX2 and MYCD can trigger both an Aβ-independent brain hypoperfusion and Aβ accumulation mediating neuronal dysfunction. Interestingly, hypoxia seems to be upstream to both, a diminished MEOX2 expression in BEC and an increased MYOCD expression in VSMCs. Adapted from [174].
Figure 2
Figure 2. The role of blood-brain barrier transport in homeostasis of brain Aβ
Brain Aβ is regulated by multiple mechanisms including: (1) central and (2) systemic production from its precursor protein APP; (3) oligomerization and aggregation; (4) receptor-mediated re-entry across the BBB into the brain via the receptor for advanced glycation end products (RAGE) (5) receptor-mediated vascular clearance across the BBB via LRP1; (6) Aβ binding to apoE, α2-macroglobulin (α2M) and apoJ in brain interstitial fluid (ISF) which influences Aβ clearance and aggregation; (7) LRP2-mediated efflux of Aβ-apoJ complexes from brain; (8) ABCB1 at the luminal side may contribute to Aβ efflux from endothelium to blood; (9) enzymatic degradation by neprilysin (NEP), insulin-degrading enzyme (IDE), tissue plasminogen activator (tPA), matrix MMPs; (10) cellular degradation by astrocytes and microglia; (11) LRP1- and LRP2-mediated transport across the choroid plexus; (12) slow removal via the ISF–CSF bulk flow; (13) sequestration in plasma by soluble LRP1 (sLRP1), which is a major Aβ binding protein in plasma; (14) removal by the liver and kidneys. Modified from [8].
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Querfurth HW, LaFerla FM. Alzheimer’s disease. The New England journal of medicine. 2010;362:329–344. - PubMed
    1. Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nature reviews. Neuroscience. 2007;8:663–672. - PubMed
    1. Ittner LM, Gotz J. Amyloid-beta and tau--a toxic pas de deux in Alzheimer’s disease. Nature reviews. Neuroscience. 2011;12:65–72. - PubMed
    1. Zlokovic BV. Neurovascular mechanisms of Alzheimer’s neurodegeneration. Trends Neurosci. 2005;28:202–208. - PubMed
    1. Zlokovic BV. Neurodegeneration and the neurovascular unit. Nat Med. 2010;16:1370–1371. - PubMed

Publication types

MeSH terms

Substances