title: Angiotensin type 1a receptor deficiency decreases amyloid β-protein generation and ameliorates brain amyloid pathology.
abstract: 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.
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.
authors.forename: Junjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.
authors.forename: Yukino
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Murakami
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sugakawa
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kami
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Tanabe
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.
authors.forename: Tomoji
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Department of Biochemistry, Nagoya City University Medical School, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Michikawa
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Komano
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.
authors.forename: Kun
authors.initials: K
authors.lastname: Zou
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000682:Amyloid / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D058225:Plaque, Amyloid / Q000235:genetics / Q000473:pathology; D066263:Protein Aggregation, Pathological / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053829:Amyloid Precursor Protein Secretases