Brain-derived neurotrophic factor supports pericyte and vascular homeostasis in the aging brain

Abstract

Microvascular circulation in the brain is often impaired in connection with the loss of pericytes in old age. The neurotrophic factor BDNF also decreases in the aging brain. We hypothesized that BDNF regulates the homeostasis of cerebral pericytes and microvasculature. We used differently aged C57BL/6J mice, and C57BL6 mice with conditional knockout of Bdnf gene. Collagen IV-positive microvessels and PDGFR{beta}-positive pericytes in the brain were counted after immunological staining. Pericytes were also quantified by Western blot of PDGFR{beta} and CD13 in isolated cerebral microvessels. The level of BDNF and TrkB phosphorylation was determined in brain homogenates. To demonstrate the direct effect of BDNF on pericytes, TrkB and pericytes were co-stained in brain tissue, single-cell sequencing and transcriptomic analysis were used to identify and characterize Ntrk2-expressing pericytes, and TrkB was also detected in the pericyte cell line by Western blot. Cultured pericytes were further treated with recombinant BDNF in the presence and absence of an Akt inhibitor and examined for PDGFR{beta} expression. The length and branching of microvessels and pericytes decreased in conjunction with the reduction in mature BDNF and TrkB phosphorylation in aging brains. Deficiency of BDNF in neurons or astrocytes was sufficient to reduce cerebral microvessels, PDGFR{beta} and CD13 concentrations and Akt and Erk1/2 phosphorylation in isolated blood vessels. A subset of pericytes in the brain and cultured pericytes expressed TrkB. BDNF treatment increased PDGFR{beta} expression along with Akt and Erk1/2 phosphorylation in cultured cells. The effect of BDNF on PDGFR{beta} expression was abolished by treatment with Akt inhibitor. Therefore, BDNF induces the expression of PDGFR{beta} and CD13 by activating Akt signaling in pericytes, promoting the homeostasis of pericytes and microvasculature in the aging brain. Our study identified a BDNF-mediated mechanism that regulates microvascular integrity in the aged brain.