The brain RAS and Alzheimer's disease

Alzheimer's disease (AD) has become a major world-wide health problem with ever rising costs associated with the treatment and care of afflicted individuals. As life expectancy has increased the occurrence of dementia has also increased. Hypertension during middle adulthood is correlated with a significantly elevated risk of cognitive impairment later in life. Treatment with antihypertensive drugs, particularly angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), has been reported to reduce the likelihood and slow the progression of AD; however, the use of ACE inhibitors may be accompanied by an increase in amyloid protein(1-42) accumulation. This review summarizes available information regarding the brain renin-angiotensin system (RAS), and specifically the efficacy of ACE inhibitors as anti-dementia agents, and considers the recently discovered AT(4) receptor and associated agonist drugs as potential new therapeutic targets to treat memory impairments associated with AD. We conclude with a description of recent efforts by members of our laboratory to develop blood-brain barrier penetrant angiotensin IV analogue drugs that facilitate cognition in animal models of AD. These efforts have resulted in a small molecule with desirable hydrophobicity characteristics that shows promise with respect to memory facilitation when peripherally administered. (C) 2009 Elsevier Inc. All rights reserved.