Losartan-induced hypotension leads to tau hyperphosphorylation and memory deficit.
Recent studies have reported a correlation between dementia and low blood pressure. How hypotension is associated with the increased risk of Alzheimer's disease (AD) remains unclear. Here we show that one month treatment of losartan, an angiotensin II type 1 (AT1) receptor antagonist, causes chronic and sustained hypotension, along with oxidative stress in adult male Sprague-Dawley rats. Furthermore, we show that losartan treatment increases the level of inactivated protein phosphatase 2A (PP2A) and the hyperphosphorylation of tau at Ser 199 and Ser 396. Rats treated with losartan present memory deficits and decreases in spine-density. These findings suggest that losartan-induced hypotension may increase the risk of AD-like pathological alteration and behavioral impairment through oxidative stress which leads to tau hyperphosphorylation and loss of dendritic spines.
Department of Pathophysiology, Key Laboratory of Neurological Disease of National Education Ministry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Xinghua
X
Liu
Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Zhihong
Z
Wang
Department of Pathophysiology, Key Laboratory of Neurological Disease of National Education Ministry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Yiyuan
Y
Xia
Department of Pathophysiology, Key Laboratory of Neurological Disease of National Education Ministry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Guang
G
Yu
Department of Pathophysiology, Key Laboratory of Neurological Disease of National Education Ministry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Kuan
K
Zeng
Department of Pathophysiology, Key Laboratory of Neurological Disease of National Education Ministry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hongbin
H
Luo
Department of Pathophysiology, Key Laboratory of Neurological Disease of National Education Ministry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Jichang
J
Hu
Department of Pathophysiology, Key Laboratory of Neurological Disease of National Education Ministry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
Cheng-Xin
CX
Gong
Department of Pathophysiology, Key Laboratory of Neurological Disease of National Education Ministry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Jian-Zhi
JZ
Wang
Department of Pathophysiology, Key Laboratory of Neurological Disease of National Education Ministry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Xin-Wen
XW
Zhou
Department of Pathophysiology, Key Laboratory of Neurological Disease of National Education Ministry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Xiao-Chuan
XC
Wang
D047228:Angiotensin II Type 1 Receptor Blockers / Q000633:toxicity*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D006973:Hypertension / Q000139:chemically induced* / Q000473:pathology; D019808:Losartan / Q000633:toxicity*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D016875:tau Proteins; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D019808:Losartan
Alzheimer's disease; hypotension; losartan; memory deficit; oxidative stress; tau hyperphosphorylation