Actions of the Anti-Angiogenic Compound Angiostatin in an Animal Model of Alzheimer’s Disease

Jae      K Ryu; Jonathan      P Little; Andis      Klegeris; Nattinee      Jantaratnotai; James      G McLarnon

doi:10.2174/1567205011310030004

Abstract

We have examined the anti-angiogenic compound, angiostatin as a modulator of inflammatory reactivity and vascular responses and for neuroprotection in an animal model of Alzheimer’s disease (AD). Intra-hippocampal amyloidbeta (Aβ_1-42) injection, relative to controls phosphate buffer saline (PBS) or reverse peptide Aβ_42-1, increased gliosis in the molecular layer (ML) of rat hippocampus. Vascular remodeling was indicated from increased microvessel immunoreactivity (ir) in ML suggesting the possibility of an angiogenic response to peptide injection. Administration of Aβ_1-42 also induced a loss of neurons in the granule cell region of hippocampus relative to controls. Treatment of peptide-injected rats with angiostatin was associated with a spectrum of modulatory effects including reduced microgliosis (by 34%), diminished microvessel ir (by 36%) and increased neuronal viability (by 31%) compared with peptide injection alone. Angiostatin treatment was ineffective in reducing astrogliosis induced by Aβ_1-42 and applied alone the compound had no significant effect to alter gliosis, microvessel ir or neuronal viability compared with PBS control. In vitro, angiostatin significantly attenuated secretion of the pro-angiogenic agent, vascular endothelial growth factor (VEGF) in lipopolysaccharide (LPS)-stimulated THP-1 cells. Our findings provide novel evidence for a broad spectrum of angiostatin effects in an animal model of AD including actions to reduce inflammatory reactivity, stabilize vascular remodeling and confer neuroprotection. The overall effects of angiostatin are consistent with actions of the compound to inhibit microglial secretion of VEGF.

Keywords: AD animal model, intrahippocampal injection of Aβ_1-42, microgliosis, vascular perturbations, angiostatin, antiangiogenic, vascular endothelial growth factor, immunohistochemistry