Candesartan treatment preserves learning and working memory in female TgF344-AD rats

Abstract

Background: Targeting the renin angiotensin system, especially with angiotensin receptor II blockers (ARB), and related vascular dysfunction is a promising therapeutic intervention for cognitive impairment including Alzheimers Disease (AD). The underlying mechanisms of the effects of ARB is unclear. This study sought to examine if treatment with candesartan, an ARB, affects neurobehavioral manifestation and the underlying neuro- and vascular mechanisms in male and female TgF344-AD rats. Methods: Candesartan or vehicle was administered to TgF344-AD rats (n=127) daily from 12-months to 18-months of age. Behavioral assays (spontaneous alternation test, novel object recognition, water radial arm maze) and neuropathologic assessment were completed along with brain proteome and measures of contractility in 12- and 18-month rat brains. Results: Untreated 18-month TgF344-AD showed impairments in learning and increased perseverative working memory errors on the water radial arm maze (WRAM). These behavioral changes were corrected with candesartan treatment in female rats only. Treatment with candesartan was also associated with improved vascular reactivity and reduced blood pressure in both wild type and TgF344-AD male and female rats. Although there was no effect on amyloid-β treatment with candesartan reduced whole brain clusterin, an AD-risk associated protein, and GFAP in female TgF344-AD. Conclusions: Our results demonstrate that candesartan administered in the early stages of AD has a sexual dimorphic response in Tgf344-AD rat, where it reduced cognitive disturbances only in female TgF344-AD rat. These effects appear to be independent of changes in blood pressure and amyloid-β reduction and are likely mediated through mechanisms related to clusterin and GFAP pathways.