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The Journal of Neuroscience, January 7, 2009, 29(1):3-13; doi:10.1523/JNEUROSCI.2888-08.2009

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

Jae K. Ryu,¹ Taesup Cho,^2 * Hyun B. Choi,^1 * Yu Tian Wang,² and James G. McLarnon¹

¹Department of Anesthesiology, Pharmacology, and Therapeutics and ²Brain Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3

Correspondence should be addressed to Dr. James G. McLarnon, Department of Anesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, 2176 Health Sciences Mall, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3. Email: mclarnon{at}interchange.ubc.ca

We hypothesize that microglial chemotactic responses to amyloid-β peptide (Aβ_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 Aβ_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 Aβ_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 Aβ 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.

Key words: VEGF receptor Flt-1; VEGF; microglia; chemotaxis; amyloid-β peptide; Alzheimer's disease; chronic inflammation

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Received June 23, 2008; revised Sept. 18, 2008; accepted Oct. 17, 2008.

Correspondence should be addressed to Dr. James G. McLarnon, Department of Anesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, 2176 Health Sciences Mall, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3. Email: mclarnon{at}interchange.ubc.ca

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