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

被引:103
作者
Ryu, Jae K.
Cho, Taesup [2 ]
Choi, Hyun B.
Wang, Yu Tian [2 ]
McLarnon, James G. [1 ]
机构
[1] Univ British Columbia, Fac Med, Dept Anesthesiol Pharmacol & Therapeut, Vancouver, BC V6T 1Z3, Canada
[2] Univ British Columbia, Vancouver Coastal Hlth Res Inst, Brain Res Ctr, Vancouver, BC V6T 1Z3, Canada
关键词
VEGF receptor Flt-1; VEGF; microglia; chemotaxis; amyloid-beta peptide; Alzheimer's disease; chronic inflammation; ENDOTHELIAL GROWTH-FACTOR; AMYLOID-BETA-PEPTIDE; BLOOD-BRAIN-BARRIER; PURINERGIC P2X(7) RECEPTOR; INJECTED RAT HIPPOCAMPUS; RHEUMATOID-ARTHRITIS; TYROSINE KINASE; GENE-EXPRESSION; ANIMAL-MODEL; DAMAGE;
D O I
10.1523/JNEUROSCI.2888-08.2009
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
We hypothesize that microglial chemotactic responses to amyloid-beta peptide (A beta(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 A beta(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 A beta(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 A beta 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.
引用
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页码:3 / 13
页数:11
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