Microglial VEGF Receptor Response Is an Integral Chemotactic Component in Alzheimer's Disease Pathology

Abstract

We hypothesize that microglial chemotactic responses to amyloid-beta peptide (Abeta(1-42)) serve as an early and integral component of inflammatory response in Alzheimer's disease (AD) brain. This study reports a receptor for vascular endothelial growth factor (VEGF), termed VEGF-1 (Flt-1), subserves microglial chemotactic responses induced by Abeta(1-42) stimulation, in vivo and in vitro. Expression of Flt-1 was significantly increased in tissue obtained from AD patients [compared with tissue from nondemented (ND) individuals], in Abeta(1-42)-injected rat hippocampus, and in peptide-stimulated human microglia. Single and double immunohistochemical staining demonstrated marked immunoreactivity, for both Flt-1 and its ligand VEGF, in association with microglia and Abeta deposits in AD, but not ND, brain tissue. Functionally, treatment with anti-Flt-1 antibody was highly effective in inhibiting microglial mobility and chemotactic responses measured in vitro using a transwell migration assay. In vivo, transplanted enhanced green fluorescent protein (EGFP)-labeled microglia exhibited Flt-1-dependent chemotaxis induced by peptide injection with anti-Flt-1 effective in blocking migration of cells. Importantly, anti-Flt-1 reduction of microglial mobility was neuroprotective in peptide-injected hippocampus and associated with a significant increase in numbers of viable hippocampal neurons. The results of this study suggest critical functional roles for Flt-1 in mediating microglial chemotactic inflammatory responses which contribute to pathological conditions in AD brain.