Interactions between Beta-Amyloid and Pericytes in Alzheimer’s Disease

Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disorder characterized by aberrant amyloid precursor protein (APP) cleavage, pathological aggregations of beta-amyloid (A $\beta{}$ ) that make up A $\beta{}$ plaques and hyperphosphorylation of Tau that makes up neurofibrillary tangles (NFTs). Although progress has been made in research on AD, the fundamental causes of this disease have not been fully elucidated. Recent studies have shown that vascular dysfunction especially the loss of pericytes plays a significant role in the onset of AD. Pericytes play a variety of important roles in the nervous system including the regulation of the cerebral blood flow (CBF), the formation and maintenance of the blood–brain barrier (BBB), angiogenesis, and the clearance of toxic substances from the brain. Pericytes participate in the transport of A $\beta{}$ through various receptors, and A $\beta{}$ acts on pericytes to cause them to constrict, detach, and die. The loss of pericytes elevates the levels of A $\beta{}$ 1-40 and A $\beta{}$ 1-42 by disrupting the integrity of the BBB and reducing the clearance of soluble A $\beta{}$ from the brain interstitial fluid. The aggravated deposition of A $\beta{}$ further exacerbates pericyte dysfunction, forming a vicious cycle. The combined influence of these factors eventually results in the loss of neurons and cognitive decline. Further exploration of the interactions between pericytes and A $\beta{}$ is beneficial for understanding AD and could lead to the identification of new therapeutic targets for the prevention and treatment of AD. In this review, we explore the characterization of pericytes, interactions between pericytes and other cells in the neurovascular unit (NVU), and the physiological functions of pericytes and dysfunctions in AD. This review discusses the interactions between pericytes and A $\beta{}$ , as well as current and further strategies for preventing or treating AD targeting pericytes.

Keywords

Alzheimer's disease

pericytes

beta-amyloid

cerebral blood flow

blood-brain barrier

neurovascular unit

cognitive decline

Funding

82101487/National Natural Science Foundation of China

ZR2021QH161/Natural Science Foundation of Shandong Province

tsqn202211318/Taishan Scholar Program of Shandong Province

Figures

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Fig. 1.

The interactions between A $\beta{}$ and pericytes. (A) LRP-1 and P-gp mediate the efflux of A $\beta{}$ while RAGE regulate the influx of A $\beta{}$ into brain parenchyma. BACE1 on pericytes degrades A $\beta{}$ 1-40 into A $\beta{}$ 34 intermediates and the A $\beta{}$ (1-42)-RAGE interaction induces the generation of VEGF and MCP-1 contributing to the vascular remodeling. (B) CD36 mediates the clearance of A $\beta{}$ 1-40 by pericytes. The reduced expression of CD36 promotes the deposition of A $\beta{}$ 1-40 resulting in CAA. (C) Oligomeric A $\beta{}$ 1-42 activates NOX4 in pericytes to produce ROS and ET in sequence, and ET binds to ET ${}_{\text{A}}$ -R on pericytes, triggering capillary constriction. Capillary constriction results in the reduction of CBF and the glucose and oxygen it contains. Hypoxia in turn upregulates the expression of BACE1, further increasing the generation of A $\beta{}$ and forming an amplified positive loop, ultimately leading to synapse dysfunction and neuron loss. (D) Fibrillar A $\beta{}$ 1-42 activates MMP-9 to induce NG2 sheds from pericytes leading to the detachment of pericytes and the destruction of endothelial TJs which is the significant part of BBB. (E) A $\beta{}$ 1-40 induces pericytes mitophagy through the CD36/PINK1/Parkin pathway and increases oxidative stress in pericytes. The increased lipid ROS and iron ions caused by oxidative stress in pericytes inducing pericytes ferroptosis dependent on mitochondrial autophagy. (F) Fibrillar A $\beta{}$ 1-40 reduces the viability and proliferation of pericytes, and increases the activity of the key apoptotic proteins caspase3/7 while the effects of monomer A $\beta{}$ 1-40 are completely opposite. LRP-1, LDL receptor-related protein-1; RAGE, receptors for advanced glycation end products; A $\beta{}$ , beta-amyloid; BACE1, $\beta{}$ -site amyloid precursor protein (APP) cleaving enzyme 1; VEGF, vascular endothelial growth factor; CAA, cerebral amyloid angiogenesis; NOX4, nicotinamide adenine dinucleotide phosphate oxidase 4; ROS, reactive oxygen species; ET, endothelin; CBF, cerebral blood flow; MMP-9, matrix metalloproteinase-9; NG2, neural/glial antigen 2; TJs, endothelial tight junctions; BBB, blood–brain barrier; PINK1, PTEN-induced putative kinase 1; sAPP $\beta{}$ , soluble amyloid precursor protein beta; MCP-1, monocyte chemoattractant protein-1; ET ${}_{\text{A}}$ -R, endothelin receptor type A.

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Front. Biosci. (Landmark Ed) Print ISSN 2768-6701 Electronic ISSN 2768-6698