Ameliorative effects of a non-competitive BACE1 inhibitor TAK-070 on Aβ peptide levels and impaired learning behavior in aged rats.
We examined the effects of TAK-070, a novel non-competitive β-secretase (BACE1) inhibitor, on the levels of Aβ peptides and behavioral deficits in rats. TAK-070 reduced soluble Aβ40 and Aβ42 levels of the cerebral cortex in a time- and dose-dependent manner in young rats. We found that the insoluble Aβ42 content increased significantly with aging from 22 months old without changing Aβ40 content. TAK-070 normalized the Aβ42 levels to those in young rats when they were fed chow containing TAK-070 starting at 19 months old for 6.5 months. Repeated administration of TAK-070 to aged rats for 2 weeks ameliorated the impaired spatial learning in the Morris water maze task and reduced the levels of soluble and insoluble Aβ peptides at doses of 0.3-1mg/kg, (p.o.). Interestingly, TAK-070 significantly recovered the reduced brain synaptophysin levels in aged rats to those in young rats. Our findings support the idea that partial inhibition of BACE1 by TAK-070 exerts symptomatic as well as disease-modifying effects for the treatment of Alzheimer's disease.
Takahashi
Hideki
H
Pharmacology Research Laboratories, Takeda Pharmaceutical Company Limited, 17-85 Juso-honmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan. Takahashi_Hideki@takeda.co.jp
Fukumoto
Hiroaki
H
Maeda
Ryouta
R
Terauchi
Jun
J
Kato
Kaneyoshi
K
Miyamoto
Masaomi
M
D000284:Administration, Oral; D000375:Aging / Q000187:drug effects / Q000378:metabolism / Q000523:psychology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D013037:Spatial Behavior / Q000187:drug effects; D013550:Swimming; D016708:Synaptophysin / Q000378:metabolism; D016896:Treatment Outcome
D016229:Amyloid beta-Peptides; D001713:Biphenyl Compounds; D009281:Naphthalenes; D010446:Peptide Fragments; D016708:Synaptophysin; C551841:TAK-070; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases