Mechanisms Underlying the Cognitive Protective Effects of Exercise

Grant Winners

  • Robert Speth, M.A, Ph.D. – College of Pharmacy
  • Natalie Builes, B.S. – College of Pharmacy
  • Samantha Bergoine – Halmos College of Oceanography and Natural Sciences
  • Andrea Linares

Deans

  • Richard Dodge, Ph.D. – Halmos College of Oceanography and Natural Sciences
  • Lisa Deziel, Ph.D., Pham.D, BCPS, FASHP – College of Pharmacy

Abstract

Women who undergo bilateral oophorectomy before menopause have increased risk of developing cognitive impairment and dementia than age-matched women, with greater risk the younger the age at oophorectomy (Rocca et al. 2007). Animal models of oophorectomy reveal similar cognitive impairment (Gibbs & Johnson, 2008). The renin angiotensin system (RAS) modulates learning and memory and contributes to the cardiovascular and neuronal protective effects of aerobic exercise. This project focuses on the role of key mediators of the RAS, i.e., angiotensin II receptors (AT1R & AT2R) in mechanisms of cognitive impairment induced by ovariectomy and the cognitive protective effects of aerobic exercise in normotensive and hypertensive rats to differentiate blood pressure-dependent and -independent effects of AT1R & AT2R actions with two specific aims:

  1. To characterize and determine the role of type 1 and 2 angiotensin receptors (AT1R & AT2R) in cognitive impairment induced by ovariectomy using receptor-specific ligands. Rats will be treated chronically with angiotensin receptor blockers (ARBs) that can (losartan) or cannot (azilsartan) cross the blood-brain-barrier. Additionally, we will determine the importance of blood pressure changes in the beneficial effects of ARB treatment. Cognitive decline will be measured with a 12-arm radial maze and novel object recognition task (NORT), which measure spatial and recognition memory and in ovariectomized and sham-operated rats as age-matched controls. Cortical and hippocampal AT1R & AT2R function, cortical thickness, neurogenesis, neurite outgrowth & apoptosis will be determined in normotensive and hypertensive rats to differentiate blood pressure-dependent & independent effects. Cortical and hippocampal AT1 receptor expression will be assessed using in vitro receptor autoradiogaphy.
  2. Determine the role of AT1R & AT2R in the cognitive protective effects of aerobic exercise in cognitive impairment induced by ovariectomy. Ovariectomized normotensive and hypertensive rats will be subjected to sedentary conditions or aerobic exercise (both simple and complex) for 6 months before cognitive function and markers of AT1R & AT2R activity, cortical thickness, neurogenesis, neurite outgrowth & apoptosis in the cerebral cortex and hippocampus will be determined.

Our proposal addresses the important societal issue of cognitive decline with aging and neurodegenerative disease, with a primary focus on Alzheimer's dementia. The special relevance of our study is: 1) Our studies focus on females; 2) They model an understudied group of women at increased risk of cognitive loss due to premenopausal removal of the ovaries; 3) We bring expertise in the brain RAS and blood pressure regulation that is implicated in cognition and neuronal protective effects of aerobic exercise albeit understudied in mechanisms of cognitive impairment and Alzheimer's disease; and, 4) We are focusing on a non-pharmacological as well as pharmacological interventions for cognitive protection - namely, aerobic exercise and RAS inhibition, which have not been studied in ovariectomy-induced cognitive impairment.