Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease

Abstract

Vascular insults can initiate a cascade of molecular events leading to neurodegeneration, cognitive impairment, and dementia. Here, we review the cellular and molecular mechanisms in cerebral blood vessels and the pathophysiological events leading to cerebral blood flow dysregulation and disruption of the neurovascular unit and the blood-brain barrier, which all may contribute to the onset and progression of dementia and Alzheimer's disease (AD). Particularly, we examine the link between neurovascular dysfunction and neurodegeneration including the effects of AD genetic risk factors on cerebrovascular functions and clearance of Alzheimer's amyloid-β peptide toxin, and the impact of vascular risk factors, environment, and lifestyle on cerebral blood vessels, which in turn may affect synaptic, neuronal, and cognitive functions. Finally, we examine potential experimental treatments for dementia and AD based on the neurovascular model, and discuss some critical questions to be addressed by future studies. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

Keywords: Alzheimer's disease; Blood–brain barrier; Dementia; Neurovascular medicine; Neurovascular unit; Vascular factors.

Figure 1

The neurovascular unit (NVU) at the level of brain capillary is comprised of vascular cells (pericytes and endothelial cells), glia (astrocytes, oligodendrocytes, and microglia) and neurons.

Figure 2

The two-hit vascular model of Alzheimer’s disease (AD) dementia. Vascular factors, such as hypertension and diabetes, and/or genetic risk factors for AD, such as apolipoprotein E ε4 (APOE4), can all lead to cerebrovascular damage (hit 1; green boxes). Within the amyloid-β peptide (Aβ)-independent pathway, cerebrovascular damage leads to blood-brain barrier (BBB) dysfunction and accumulation of blood-derived neurotoxic molecules in the brain, from one hand, and oligemia or reduced cerebral blood volume, from the other. Additionally, within the amyloidogenic Aβ pathway, BBB dysfunction can disrupt Aβ clearance across the BBB and oligemia leads to overexpression and enhanced processing of Aβ precursor protein (APP), which both can promote Aβ accumulation in the brain (hit 2; black boxes). The converging Aβ-independent and Aβ-dependent pathways can each independently and/or synergistically lead to synaptic and neuronal dysfunction, neurodegeneration, and disruption of brain structural and functional connectivity that ultimately leads to dementia.

Figure 3

Blood-brain barrier (BBB) pathways to neurodegeneration in dementia and Alzheimer’s disease (AD). A. In the normal capillary, there is an intact BBB composed of tightly joined endothelial cells and supported by mural pericytes, as shown in this simplified schematic. The BBB normally selectively regulates the passage of molecules from blood to brain and vice versa, and restricts entry of blood-derived products and toxins into the brain. There are many transporters and receptors along the BBB that permit molecules to cross the BBB via substrate-specific transport systems, some of which are particularly relevant to AD pathophysiogenesis, as illustrated in the inset. For example, the normal BBB has high expression of the glucose transporter (GLUT1), moderate expression of low density lipoprotein receptor related protein-1 (LRP1) and minimal expression of receptor for advanced glycation end-products (RAGE). B. In the AD capillary, there is a vicious cascade of events that can lead to neurodegeneration, as shown in this schematic and described as follows. 1. Pericytes degenerate and detach. 2. The BBB becomes leaky. 3. Blood-derived molecules like fibrinogen, thrombin and plasminogen leak from vessels and are directly toxic to neurons and can further induce BBB damage. Erythrocyte extravasation induces accumulation of hemoglobin derived-iron which causes generation of reactive oxygen species (ROS) and oxidative stress to neurons, and albumin promotes local tissue edema. 4. BBB transporter expression is altered, e.g., LRP1 and GLUT1 expression are significantly reduced, whereas RAGE expression is increased. The alterations in LRP1 and RAGE reduce the clearance and increase the uptake of Aβ into the brain, respectively, leading to Aβ accumulation in the brain. Also, normal cerebrovascular functions are disrupted by vascular pathologies including 5. Cerebral amyloid angiopathy, 6. Damaged and thickening of the basement membrane, and 7. String vessels.