Angiotensin type 1a receptor deficiency decreases amyloid [beta]-protein generation and ameliorates brain amyloid pathology

• Published in: Scientific reports 2015-07, Vol.5, p.12059
• Main Authors: Liu, Junjun, Liu, Shuyu, Matsumoto, Yukino, Murakami, Saki, Sugakawa, Yusuke, Kami, Ayako, Tanabe, Chiaki, Maeda, Tomoji, Michikawa, Makoto, Komano, Hiroto, Zou, Kun
• Format: Article
• Language: English
• Subjects: Accumulation; Alzheimer's disease; Angiotensin AT1 receptors; Angiotensin II; Antihypertensives; Blood pressure; Hypertension; Medical treatment; Neurodegenerative diseases; Pathogenesis; Presenilin 1; Risk factors; Rodents; Secretase; β-Amyloid
• ISSN: 2045-2322
• DOI: 10.1038/srep12059

Alzheimer's disease is characterized by neuronal loss and cerebral accumulation of amyloid-β protein (Aβ) and lowering the generation of Aβ is a pivotal approach in the strategy of Alzheimer's disease treatment. Midlife hypertension is a major risk factor for the future onset of sporadic Alzheimer's disease and the use of some antihypertensive drugs may decrease the incidence of Alzheimer's disease. However, it is largely unknown how the blood pressure regulation system is associated with the pathogenesis of Alzheimer's disease. Here we found that the deficiency of angiotensin type 1a receptor (AT1a), a key receptor for regulating blood pressure, significantly decreased Aβ generation and amyloid plaque formation in a mouse model of Alzheimer's disease. The lack of AT1a inhibited the endocleavage of presenilin-1 (PS1), which is essential for γ-secretase complex formation and Aβ generation. Notably, the ligand of AT1a, angiotensin II, enhanced Aβ generation, PS1 endocleavage and γ-secretase complex formation. Our results suggest that AT1a activation is closely associated with Aβ generation and brain amyloid accumulation by regulating γ-secretase complex formation. Thus, removal of life style factors or stresses that stimulate AT1a to elevate blood pressure may decrease Aβ generation and brain amyloid accumulation, thereby preventing the pathogenesis of Alzheimer's disease.