VCAM1 is a Mediator of Age-related Brain Inflammation & Decreased Neurogenesis Caused by an Aged Systemic Milieu
BY Hanadie Yousef, Ph.D.
Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
Wednesday, 27 July 2016, 1:00 PM at E-Learning Unit- Yasser Arafat Building
Studies from our lab and others have recently shown that brain function – specifically neurogenesis, synaptic plasticity and cognitive function in the hippocampus, a key center for learning and memory– is inhibited in young mice connected to aged mice through heterochronic parabiosis or aged plasma intravenous injections. While the identity of systemic inhibitory factors from aged plasma are beginning to be elucidated, the question of how and if these factors cross the blood brain barrier (BBB) and act directly on brain tissue to inhibit neurogenesis, or whether they act through their direct contact with brain endothelial cells (BECs) of the vasculature remain unanswered. BECs upregulate expression of vascular adhesion molecules as a result of increased systemic inflammatory signaling resulting from multiple diseases that afflict the CNS. We discovered that BEC-specific VCAM1 increases in the hippocampus during normal aging. Exposure of young BECs to an aged systemic environment induces BEC activation and upregulation of VCAM1 both in vitro and in vivo. Specifically, systemic injections of aged human blood into young immunodeficient (NSG) mice- acutely over 4 days or spread over 3 weeks- increased BEC-specific VCAM1 expression, increased brain inflammation as assessed by microglial activation, and inhibited hippocampal neurogenesis. Blocking VCAM1 signaling systemically with a neutralizing monoclonal antibody rescued neurogenesis and prevented aged plasma induced microglial activation. This study suggests preventing BEC-immune cell crosstalk through VCAM1 may be a therapeutic target for ameliorating aged blood induced decline in brain function.