Abstract T P410: Angiopoietin-1 Mimetic Peptide Treatment Promotes White Matter Remodeling And Improves Cognitive Function In Rats With Vascular Dementia

Abstract

Background and Purpose: Vascular Dementia (VaD) affects cognitive and memory function. Clinically, a series of minor or silent strokes induce subcortical lesions and may lead to VaD. In this study, we developed a multiple microinfarct-based mild VaD model in retired breeder rats and tested the therapeutic effects of an Angiopoietin-1 mimetic peptide, Vasculotide (VT) on cognitive decline and white matter (WM) damage. Methods: Male retired breeder rats were subjected to a multiple microinfarct model (500 70-100 μm cholesterol crystals injected into the internal carotid artery) and treated with 1) PBS 2) VT (3 μg/Kg, i.p. injection) starting at 1 day for 14 days (n=6/group). Neurological and cognitive deficits were evaluated 2 and 6 weeks later. Rats were sacrificed on 7th week. Results: The multiple microinfarct model induced cognitive decline in retired breeder rats starting at 2 weeks which persisted to 6 weeks after surgery. Significant (p<0.05) loss in short term memory was observed using the Novel Object Recognition Task and memory loss was evident from the Odor Test. Anxiety-like behavior was observed during Open Field evaluation. Compared to non surgery rats, VaD significantly decreased neurite branching and spine density measured by Golgi staining; induced significant WM damage identified by decreased axon and myelin density, decreased oligodendrocyte progenitor cells and oligodendrocyte number; and decreased synaptic protein expression in the corpus callosum and striatum. VaD also significantly increased RAGE (Receptor for Advanced Glycation Endproducts) expression in the brain. Treatment of VaD with VT significantly (p<0.05) improved cognitive function and memory, decreased anxiety, significantly attenuated WM damage, increased neurite branching and spine density and synaptic protein expression as well as decreased RAGE expression compared to VaD control rats (p<0.05). Conclusion: Multiple microinfarcts can induce significant WM damage and cause decline in cognition and memory. VT treatment promotes WM remodeling, synaptic plasticity and anti-inflammation which in concert may contribute to the improvement in cognition and memory.