VEGF Paradoxically Reduces Cerebral Blood Flow in Alzheimer's Disease Mice

Abstract

Vascular dysfunction plays a critical role in the development of Alzheimer's disease. Cerebral blood flow reductions of 10% to 25% present early in disease pathogenesis. Vascular Endothelial Growth Factor-A (VEGF-A) drives angiogenesis, which typically addresses blood flow reductions and global hypoxia. However, recent evidence suggests aberrant VEGF-A signaling in Alzheimer's disease may undermine its physiological angiogenic function. Instead of improving cerebral blood flow, VEGF-A contributes to brain capillary stalls and blood flow reductions, likely accelerating cognitive decline. In this commentary, we explore the evidence for pathological VEGF signaling in Alzheimer's disease, and discuss its implications for disease therapy.

Keywords: Alzheimer’s disease; VEGF-A signaling; blood-brain barrier; cerebral blood flow.

Figure 1.

VEGF seeds leukocyte stalls in the brain microvasculature of APP/PS1 mice, leading to reduced cerebral blood flow. (A) Individual capillaries from in vivo 2-photon excited fluorescence microscopy image stacks. Capillaries were characterized as flowing or stalled based on the movement of unlabeled (black) red blood cells within the Texas Red labeled blood plasma (red) over the period of 5 seconds. (B) Z-projection of 2-photon excited fluorescence microscopy image stacks containing stalled capillaries labeled with Texas Red and Rhodamine 6G (green). Stalled capillaries contain a leukocyte (top left), platelet aggregates (top center), RBCs (top right), leukocytes and red blood cells (bottom left), leukocytes and platelets (bottom center), and platelets and red blood cells (bottom right). (C) Fraction of stalled capillaries in APP/PS1 (n = 12) and wild-type (WT) (n = 8) mice, ~23 000 capillaries; 2-tailed Mann-Whitney test, P = .001; box plot with red line representing median and black line representing mean. (D) In APP/PS1 mice amyloid-beta causes endothelial damage through reactive oxygen species, leading to increased angiogenic factor like VEGF-A. Increased VEGF-A levels leads to increased eNOS activity, downregulation of occludin, impairment of the blood-brain barrier, activation of local inflammatory markers, recruitment of leukocytes, stalling of capillary flow, and reduced cerebral blood flow. Images taken from Ali et al.

Figure 2.

VEGF contributes to leukocyte stalls at the brain-retina barrier in diabetic retinopathy. (A) Schematic of increased endothelial cell adhesion of leukocytes in diabetic retinopathy. Diabetes-associated expression of adhesion molecules (ICAM-1 and P-selectin) causes increased leukocyte-endothelial interactions and stalled capillary blood flow. (B) Evidence of 2 neutrophils entrapped in a vascular segment of a diabetic monkey’s retina. Images taken from Chibber et al.