Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease.
Recent epidemiological evidence suggests that some antihypertensive medications may reduce the risk for Alzheimer disease (AD). We screened 55 clinically prescribed antihypertensive medications for AD-modifying activity using primary cortico-hippocampal neuron cultures generated from the Tg2576 AD mouse model. These agents represent all drug classes used for hypertension pharmacotherapy. We identified 7 candidate antihypertensive agents that significantly reduced AD-type beta-amyloid protein (Abeta) accumulation. Through in vitro studies, we found that only 1 of the candidate drugs, valsartan, was capable of attenuating oligomerization of Abeta peptides into high-molecular-weight (HMW) oligomeric peptides, known to be involved in cognitive deterioration. We found that preventive treatment of Tg2576 mice with valsartan significantly reduced AD-type neuropathology and the content of soluble HMW extracellular oligomeric Abeta peptides in the brain. Most importantly, valsartan administration also attenuated the development of Abeta-mediated cognitive deterioration, even when delivered at a dose about 2-fold lower than that used for hypertension treatment in humans. These preclinical studies suggest that certain antihypertensive drugs may have AD-modifying activity and may protect against progressive Abeta-related memory deficits in subjects with AD or in those at high risk of developing AD.
Wang
Jun
J
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA.
Ho
Lap
L
Chen
Linghong
L
Zhao
Zhong
Z
Zhao
Wei
W
Qian
Xianjuan
X
Humala
Nelson
N
Seror
Ilana
I
Bartholomew
Sadie
S
Rosendorff
Clive
C
Pasinetti
Giulio Maria
GM
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D020836:Protein Structure, Quaternary; D011897:Random Allocation; D013028:Space Perception / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000959:Antihypertensive Agents; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine