The pericyte: a forgotten cell type with important implications for Alzheimer's disease?

Abstract

Pericytes are cells in the blood-brain barrier (BBB) that degenerate in Alzheimer's disease (AD), a neurodegenerative disorder characterized by early neurovascular dysfunction, elevation of amyloid β-peptide (Aβ), tau pathology and neuronal loss, leading to progressive cognitive decline and dementia. Pericytes are uniquely positioned within the neurovascular unit between endothelial cells of brain capillaries, astrocytes and neurons. Recent studies have shown that pericytes regulate key neurovascular functions including BBB formation and maintenance, vascular stability and angioarchitecture, regulation of capillary blood flow, and clearance of toxic cellular by-products necessary for normal functioning of the central nervous system (CNS). Here, we review the concept of the neurovascular unit and neurovascular functions of CNS pericytes. Next, we discuss vascular contributions to AD and review new roles of pericytes in the pathogenesis of AD such as vascular-mediated Aβ-independent neurodegeneration, regulation of Aβ clearance and contributions to tau pathology, neuronal loss and cognitive decline. We conclude that future studies should focus on molecular mechanisms and pathways underlying aberrant signal transduction between pericytes and its neighboring cells within the neurovascular unit, that is, endothelial cells, astrocytes and neurons, which could represent potential therapeutic targets to control pericyte degeneration in AD and the resulting secondary vascular and neuronal degeneration.

Keywords: Alzheimer's disease; amyloid beta; blood-brain barrier; hypoperfusion; neurodegeneration; pericytes.

Figure 1

Cerebrovascular structure and the neurovascular unit (NVU). In the brain, pial arteries travel along the cerebrospinal fluid filled subarachnoid space and give rise to penetrating intracerebral arteries, which enter the brain parenchyma but are separated from neurons and glia by the perivascular Virchow‐Robin spaces defined by an outer wall of pia and astrocyte‐derived glial limitans membrane. These arteries branch into smaller arteries, arterioles and brain capillaries distally. At a cellular level, vascular function requires coordinated cross‐talk between multiple cell types of the NVU. The NVU is composed of endothelial cells, vascular mural cells (vascular smooth muscle and pericytes), glial cells (astrocytes and microglia) and neurons. The identity of mural cells changes along the arterial–venous axis. In intracerebral arteries, vascular smooth muscle cells occupy most of the vascular wall. At the level of brain capillaries, pericytes replace smooth muscle cells and are attached to the vascular basement membrane. Pericytes extend multiple cytoplasmic processes that encircle endothelial cells. The point of transition from smooth muscle to pericyte remains poorly defined. At each level, mural cells are further surrounded by astrocyte end‐feet and are in close proximity to neurons and microglia. Figure modified from Zlokovic 196.

Figure 2

The vascular two hit hypothesis of Alzheimer's neurodegeneration. Vascular injury as result of long‐standing vascular risk factors, for example, hypertension, dyslipidemia, diabetes, smoking, or obesity, genetic risk, for example, apolipoprotein ε4, and/or other unidentified environmental or toxic injury leads to early vascular dysfunction characterized by abnormalities in endothelial cells, pericytes and vascular smooth muscle cells. Vascular cell dysfunction and/or degeneration results in hypoperfusion (oligemia) and blood–brain barrier (BBB) dysfunction (hit 1) leading to hypoxia and accumulation of multiple plasma‐derived neurotoxins, respectively, and contributes to neuronal dysfunction, degeneration and development of cognitive decline (solid lines). BBB dysfunction, mural cell loss and hypoperfusion/hypoxia reduce vascular amyloid β‐peptide (Aβ) clearance across the BBB and in vascular mural cells and increases production of Aβ from Aβ‐precursor protein (APP), causing Aβ accumulation in brain (hit 2, dashed lines). Pathologic elevations in soluble Aβ lead to the formation of neurotoxic Aβ oligomers and accelerates Aβ deposition around neurons and on blood vessels. Aβ species then amplify both vascular and neuronal injury. Tau phosphorylation and/or pathology, for example, caspase‐cleavage and/or formation of neurofibrillary tangles, within neurons results from convergence of vascular injury (hypoperfusion and BBB disruption) and direct Aβ neurotoxicity. Figure modified from Zlokovic 196.

Figure 3

Pericyte degeneration leads to a chronic BBB disruption and vascular‐mediated secondary neuronal injury and degeneration. Pericyte loss and/or degeneration represent an important cellular source of hit 1 vascular injury in Alzheimer's disease. Pericyte degeneration leads to BBB disruption and unrestricted entry and accumulation of blood‐derived products in brain including erythrocyte‐derived hemoglobin and plasma‐derived proteins such as albumin, plasmin, thrombin, fibrin, immunoglobulin and others. Plasmin and thrombin have direct neurotoxic properties, whereas fibrin accelerates neurovascular injury. Brain degradation of hemoglobin liberates free iron, which catalyzes formation of reactive oxygen species (ROS) leading to further injury. Albumin increases oncotic pressure resulting in edema, microvascular compression and reduced blood flow. Pericyte loss also leads to endothelial cell death and microvascular regression leading to additional simultaneous reductions in blood flow. In mouse models, vascular injury in absence of Aβ as a result of pericyte loss is sufficient for neurodegeneration. Figure modified from Zlokovic 196.

Figure 4

Apolipoprotein E4 triggers early pericyte dysfunction and blood–brain barrier (BBB) breakdown. Apolipoproteins are secreted by astrocytes. ApoE2 and apoE3, but not apoE4, bind to the low density lipoprotein receptor‐related protein‐1 (LRP‐1) on pericytes and suppress the levels of a pro‐inflammatory cytokine cyclophilin A (CypA). ApoE4 exhibits weak binding to LRP‐1 resulting in pathologic elevations in CypA protein levels, which, in turn, increases nuclear translocation of the pro‐inflammatory transcription factor nuclear factor‐κB (NF‐κB), and upregulation of pericyte matrix metalloproteinase‐9 (MMP‐9). Secretion and activation of MMP‐9 degrades endothelial tight and adherens junction proteins leading to disruption of the BBB. Pathologic elevations of MMP‐9 and a disrupted BBB lead to capillary loss and hypoperfusion. Vascular injury may then lead to neuronal dysfunction and degeneration. Figure modified from Bell et al 15.

Figure 5

Pericyte degeneration and loss contributes to Alzheimer's type neurodegeneration through amyloid β‐peptide (Aβ) independent and dependent injury mechanisms. Brain pericyte loss as a result of disruption of the platelet derived growth factor receptor β (PDGFRβ) signaling triggers early Aβ‐independent vascular injury leading to microvascular loss and disruption, which results in hypoperfusion/hypoxia and brain accumulation of toxic plasma proteins, respectively (black). Loss of pericytes also leads to diminished clearance of soluble Aβ species from brain interstitial fluid (ISF) and further elevations in brain Aβ levels (red). Aβ may then overwhelm degradative pathway in surviving pericytes, resulting in further pericyte degeneration (dashed line). Both pericyte loss and Aβ acting simultaneously result in the early development of all facets of Alzheimer's disease neuropathology including Aβ plaques and neuronal tau pathology, degeneration and loss, which are not observed at an early disease stage when Aβ accumulation or pericyte‐driven vascular injury occurs in isolation. Figure modified from Sagare et al 139.