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    116—Alzheimer's Disease: Neuroinflammation and Immune Mechanisms

    Sunday, November 10, 2013, 8:00 am - 11:30 am

    116.10: VEGF exacerbates blood-brain barrier dysfunction and neuroinflammation in the cellular and mouse models of Alzheimer’s disease

    Location: 33C

    1Dept. of Pediatrics, 2Dept. of Neurosurg., Univ. of Rochester Med. Ctr., Rochester, NY; 3Dept. of Physiol. and Biophysics, USC, Los Angeles, CA; 4Inst. of Physiol. and Pathophysiology, Heidelberg, Germany

    Abstract Body: Alzheimer’s disease (AD) brains show reduced regional cerebral blood flow (CBF) and localized hypoxia. Tissue hypoxia resulting from poor blood circulation is linked to hypoxia-inducible factor 1 alpha mediated upregulation of vascular endothelial growth factor (VEGF), a potent pro-angiogenic factor. Our studies with cellular models of blood-brain barrier indicated that VEGF potentiates the amyloid-beta induced loss of barrier function. VEGF also increase the infiltration of microglial cells across the endothelial cell monolayer. To study the role of VEGF in the mouse model of AD we overexpressed neuronal VEGF in brain by crossing TgAPP sw+/- mice with the mice overexpressing neuronal VEGF (TgVEGF). TgAPP-VEGF mice showed increase in blood-brain permeability and accumulation of blood-derived neurotoxins in brain. Pericyte coverage on the cerebral microvessels was significantly reduced in TgAPP-VEGF mice. The blood-brain barrier breakdown in these mice was also associated with increase in adhesion molecules on the microvessels and induction of activated microglia as well as pro-inflammatory cytokines and chemokines. Behavioral analysis showed reduction of cognitive functions in these mice. These findings suggest that chronic increase of VEGF in AD could contribute to blood-brain barrier breakdown and neuroinflammation.

    Lay Language Summary: A study conducted at the University of Rochester Medical Center has found that a secreted protein produced during characteristic restricted blood flow in Alzheimer’s brains can increase disease severity.
    In healthy tissues a secreted protein called vascular endothelial growth factor (VEGF) promotes the formation of new blood vessels during low oxygen availability. Localized hypoxia resulting from poor blood circulation in Alzheimer’s brain can also induce the secretion of VEGF in brain. Our study suggests the harmful effects of sustained increase of VEGF in the presence of amyloid beta, the signature toxic protein in Alzheimer brains. The work offers important insights into potential ways to address blood flow difficulties, which many scientists feel is at the core of Alzheimer’s disease pathogenesis.
    Much evidence indicates that Alzheimer’s disease is associated with the abnormal buildup of amyloid proteins in the brain as well as localized hypoxia. But it remains unclear how exactly hypoxia-induced VEGF and amyloid beta together affect cognitive decline in this condition.
    In a normal brain, different kinds of cells form a structural barrier between the blood and the brain parenchyma. This blood-brain barrier acts as a gatekeeper that strictly controls the transport of molecules and gives the brain a unique microenvironment. We first studied the interactions between VEGF and amyloid beta in human brain endothelial cells that form the protective barrier between the blood and brain. We observed that barrier formed by cultured endothelial cells got damaged following treatment with VEGF and amyloid. This treatment also induced endothelial cells to express molecules that attract inflammatory cells and allowed their passage through the barrier, something an intact barrier would rarely allow.
    To mimic chronic disease conditions as found in Alzheimer’s disease, we developed a genetically engineered mouse overexpressing neuron specific VEGF along with amyloid accumulation in brain. These mice showed deterioration of blood-brain barrier as compared to mice with only amyloid accumulation. We observed that VEGF promotes vascular leakage and infiltration of blood-borne neurotoxins and other potentially harmful agents into the brains of these transgenic mice. We also found impairment to pericytes, the specialized cells that cover endothelial cells and help in maintaining the integrity of blood-brain barrier. This study explains how VEGF can contribute to deterioration of blood-brain barrier as observed in Alzheimer’s disease.
    Mice with both VEGF and amyloid beta showed increased levels of molecules on blood vessels that would increase cellular infiltration in the brain as well as increase in inflammatory cells in the brain. The mice also demonstrated exaggerated activation of microglia and astrocytes, the glial cells of the brain, which release factors that enhance neuronal damage. Behavioral analysis of these mice showed defects in cognition.
    We have also characterized the underlying mechanism of these effects, and describe a novel receptor and the downstream molecular signaling cascade. Our findings suggest that chronic increase of VEGF in Alzheimer’s disease can damage the blood-brain barrier that leads to neuroinflammation and cognitive deficits in Alzheimer’s disease. In summary, we report a novel pathway that leads to impairment in the blood-brain barrier and causes exacerbated pathology and cognitive problems in a mouse model of Alzheimer’s disease.