Treatment with AV‐001, an Angiopoietin‐1 mimetic peptide, improves dementia outcomes in rats

Abstract

AbstractBackgroundVascular dementia (VaD) is a complex neurodegenerative disease affecting cognition and memory. We investigated the neurocognitive outcomes of multiple‐microinfarct (MMI) dementia in aged female rats. We previously found that treatment with AV‐001, a Tie2 receptor agonist, significantly improves memory and preference for social novelty in middle‐aged male rats subjected to MMI. In this study, we tested the therapeutic effects of AV‐001 in aged female rats subjected to MMI.MethodFemale, Wistar, rats were aged to 18m and randomly assigned to Sham, MMI, and MMI+1µg/Kg AV‐001 treatment groups (n = 8‐9/group). MMI was induced by injecting either 1000 (low dose, LD‐MMI) or 6000 (high dose, HD‐MMI), 70‐100µm sized cholesterol crystals into the internal carotid artery. AV‐001 treatment (1µg/Kg, i.p.) was initiated at 1d after MMI and administered once daily. A battery of neuro‐cognitive tests was performed at 21‐28d MMI.ResultLD‐MMI induces significant (p<0.05) neurological deficits evaluated using the modified neurological severity score (mNSS) test, starting at 1d after LD‐MMI and persisting at least up to 28d after LD‐MMI. Treatment of LD‐MMI with AV‐001 significantly improves neurological function at 21d and 28d after LD‐MMI compared to LD‐MMI control rats. Aged female rats subjected to LD‐MMI exhibit long term memory impairment in an olfactory learning based novel odor recognition test and a significantly lower preference for social novelty in the three‐chamber social test, although there were no changes in overall preference for sociability compared to Sham rats. Treatment of LD‐MMI with AV‐001 significantly improves long‐term memory and preference for social novelty compared to LD‐MMI control rats. HD‐MMI in aged female rats induces significant anxiety‐ and depression‐like behavior with increased freezing time in the open field test and decreased time spent in the open arms of the elevated plus maze compared to Sham rats. Treatment of HD‐MMI with AV‐001 significantly reduces anxiety like behavior indicated by increased time spent in the open arms of the elevated plus maze compared to HD‐MMI control rats.ConclusionAV‐001 is a novel therapeutic agent that may improve neurological deficits, memory impairment, and anxiety like behavior in aged female rats subjected to a MMI model of vascular dementia.