amyloid-beta-peptides and olmesartan

Angiotensin II receptor blockers (ARBs) are widely prescribed for the medication of systemic hypertension and congestive heart failure. It has been reported that ARBs can reduce the risk for the onset of Alzheimer's disease (AD) and have beneficial effects on dementia. Neurotoxic amyloid β-protein (Aβ) is believed to play a causative role in the development of AD. However, whether ARBs regulate Aβ generation remains largely unknown. Here, we studied the effect of ARBs on Aβ generation and found that telmisartan significantly increased Aβ40 and Aβ42 generation, but decreased the Aβ42/Aβ40 ratio. However, losartan, valsartan and candesartan did not increase Aβ generation, while olmesartan significantly increased Aβ42 generation. We also found that telmisartan increased the Aβ generation through angiotensin type 1a receptor (AT1a) and the receptor-related phosphotidylinositide 3-kinases (PI3K) pathway. Our findings revealed the different effects of ARBs on Aβ generation and provide new evidence for the relationship between antihypertensive treatment and AD pathogenesis.

Topics: Amyloid beta-Peptides; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Benzoates; Biphenyl Compounds; Cells, Cultured; Fibroblasts; Imidazoles; Losartan; Mice, Inbred C57BL; Mice, Knockout; Peptide Fragments; Phosphatidylinositol 3-Kinases; Receptor, Angiotensin, Type 1; Signal Transduction; Telmisartan; Tetrazoles; Valine; Valsartan

Recent studies suggest that vascular risk factors play a considerable role in the development of Alzheimer disease. Furthermore, the use of antihypertensive drugs has been suggested to reduce the incidence of dementia, including Alzheimer disease. In this study, we examined the effects of an angiotensin receptor blocker, olmesartan, on beta-amyloid-induced cerebrovascular dysfunction and cognitive impairment. Oral administration of a low dose of olmesartan attenuated cerebrovascular dysfunction in young Alzheimer disease-model transgenic mice (APP23 mouse), without a reduction in the brain beta-amyloid level. Moreover, treatment of APP23 mice with olmesartan decreased oxidative stress in brain microvessels. Using an acute mouse model induced by ICV administration of beta-amyloid 1-40, we assessed the effect of oral administration of olmesartan on spatial learning evaluated with the Morris water maze. Olmesartan significantly improved cognitive function independent of its blood pressure-lowering effect, whereas there was no improvement by other types of antihypertensive drugs (hydralazine and nifedipine). We found that pretreatment with a low dose of olmesartan completely prevented beta-amyloid-induced vascular dysregulation and partially attenuated the impairment of hippocampal synaptic plasticity. These findings suggest the possibility that amelioration of cerebrovascular dysfunction with an angiotensin receptor blocker could be a novel therapeutic strategy for the early stage of Alzheimer disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Angiotensin II Type 1 Receptor Blockers; Animals; Cerebrovascular Circulation; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Hippocampus; Imidazoles; Male; Maze Learning; Mice; Mice, Transgenic; Microcirculation; Neuronal Plasticity; Oxidative Stress; Peptide Fragments; Reactive Oxygen Species; Renin-Angiotensin System; Tetrazoles