Neurovascular dysfunction and faulty amyloid β-peptide clearance in Alzheimer disease

Abstract

Neurovascular dysfunction is an integral part of Alzheimer disease (AD). Changes in the brain vascular system may contribute in a significant way to the onset and progression of cognitive decline and the development of a chronic neurodegenerative process associated with accumulation of amyloid β-peptide (Aβ) in brain and cerebral vessels in AD individuals and AD animal models. Here, 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 blood-brain barrier (BBB) dysfunction, decreased cerebral blood flow, and impaired vascular clearance of Aβ from brain. The data reviewed here support an essential role of the neurovascular and BBB mechanisms in AD pathogenesis.

Figure 1.

The vascular hypothesis of Alzheimer disease. Vascular risk factors (e.g., hypertension, diabetes, obesity, cardiac disease) and/or an initial vascular damage mediated by a cerebrovascular disorder (e.g., ischemia, stroke) lead to brain hypoperfusion (oligemia) and/or blood–brain barrier (BBB) dysfunction (hit 1), which is associated with a diminished brain capillary flow/hypoxia and accumulation of multiple neurotoxins in brain, respectively, that can impact neuronal function contributing to the development of neurodegenerative changes and cognitive decline (solid lines). In a parallel pathway, BBB dysfunction and hypoperfusion/hypoxia can reduce amyloid β peptide (Aβ) vascular clearance across the BBB and increase Aβ production from Aβ-precursor protein (APP), respectively, causing Aβ accumulation in brain (hit 2; dashed lines). Elevated Aβ levels lead to formation of neurotoxic Aβ oligomers, causing neuronal dysfunction, on the one hand, and self-aggregation, on the other, which leads to self-propagation of Aβ-mediated brain disorder and the development of cerebral β-amyloidosis. According to the vascular hypothesis, a pathogenic tau phosphorylation in neurons and the development of tau-related pathology including neurofibrillary tangles (not shown in the diagram) may be triggered independently or simultaneously by a hypoperfusion/hypoxia insult and/or direct Aβ neurotoxicity.

Figure 2.

The neurovascular unit and neurovascular functions. (A) A schematic illustration of the neurovascular unit at the level of brain capillary consisting of brain endothelial cells, pericytes, astrocytes, microglia, and neurons. Endothelial cells and pericytes share a common basement membrane and form direct “peg and socket” contacts. Astrocyte end-feet processes ensheath the capillary wall made up of pericytes and endothelial cells. (B) Vascular cells (endothelium and pericytes), glia (e.g., astrocytes), and neurons regulate multiple neurovascular functions. (Modified from Zlokovic 2008.)

Figure 3.

The role of blood–brain barrier (BBB) transport in homeostasis of brain Aβ. Influx pathway: RAGE, the receptor for advanced glycation end products, mediates influx and reentry of circulating Aβ across the BBB. RAGE-mediated Aβ influx is accompanied by generation of reactive oxygen species (ROS) and activation of nuclear factor-κB (NF-κB)-mediated inflammatory response in endothelium, that is, increased production of cytokines including tumor necrosis factor α (TNFα), interleukin (IL) 1β and 6, and monocyte chemotactic protein-1 (MCP1), as well as increased expression of several leukocyte adhesion molecules (not shown). RAGE also mediates transport of Aβ-laden monocytes across the BBB. Efflux pathway: LRP, the low-density lipoprotein receptor-related protein-1, mediates Aβ clearance from brain via transport of free Aβ and Aβ-bound to apoE2 and apoE3, but not apoE4, across the BBB. Other Aβ transport proteins in brain interstitial fluid such as apoJ and α-2 macroglobulin (α2M) influence Aβ clearance from brain. Aβ enzymatic clearance, oligomerization, and aggregation also control Aβ levels in brain. Soluble form of LRP (sLRP) in plasma is a major binding protein of plasma Aβ. sLRP is produced by the proteolytic cleavage from LRP mediated by β-secretase (BACE). Liver and kidneys mediate systemic clearance of free Aβ and of sLRP–Aβ complexes. APP, Aβ-precurosr protein. TJ, tight junctions. (Modified from Zlokovic 2008.)

Figure 4.

Alterations in vascular-specific gene expression mediating neurovascular dysfunction in AD. (Left) Hypoxia down-regulates mesenchyme homeobox gene-2 (MEOX2) in brain endothelial cells (BEC). 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 LRP, a major Aβ clearance receptor, leading to a loss of LRP from BEC and reduced Aβ clearance from brain. (Right) Hypoxia increases expression of myocardin (MYOCD) in vascular smooth muscle cells (VSMCs) resulting in elevated levels of MYOCD and serum response factor (SRF). 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 LRP. Loss of LRP 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. It is of note that 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.