Fig. 1.The interactions between A and pericytes. (A) LRP-1
and P-gp mediate the efflux of A while RAGE regulate the influx of
A into brain parenchyma. BACE1 on pericytes degrades A1-40 into
A34 intermediates and the A (1-42)-RAGE interaction induces the
generation of VEGF and MCP-1 contributing to the vascular remodeling. (B) CD36
mediates the clearance of A1-40 by pericytes. The reduced expression of
CD36 promotes the deposition of A1-40 resulting in CAA. (C) Oligomeric
A1-42 activates NOX4 in pericytes to produce ROS and ET in sequence, and
ET binds to ET-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 and forming an amplified positive loop, ultimately
leading to synapse dysfunction and neuron loss. (D) Fibrillar A1-42
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) A1-40 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 A1-40 reduces the
viability and proliferation of pericytes, and increases the activity of the key
apoptotic proteins caspase3/7 while the effects of monomer A1-40 are
completely opposite. LRP-1, LDL receptor-related protein-1; RAGE, receptors for
advanced glycation end products; A, beta-amyloid; BACE1, -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, soluble amyloid precursor protein
beta; MCP-1, monocyte chemoattractant protein-1; ET-R, endothelin receptor
type A.