Abstract
We discovered a nonpeptidic compound, TAK-070, that inhibited BACE1, a rate-limiting protease for the generation of Abeta peptides that are considered causative for Alzheimer's disease (AD), in a noncompetitive manner. TAK-070 bound to full-length BACE1, but not to truncated BACE1 lacking the transmembrane domain. Short-term oral administration of TAK-070 decreased the brain levels of soluble Abeta, increased that of neurotrophic sAPPalpha by approximately 20%, and normalized the behavioral impairments in cognitive tests in Tg2576 mice, an APP transgenic mouse model of AD. Six-month chronic treatment decreased cerebral Abeta deposition by approximately 60%, preserving the pharmacological efficacy on soluble Abeta and sAPPalpha levels. These results support the feasibility of BACE1 inhibition with a noncompetitive inhibitor as disease-modifying as well as symptomatic therapy for AD.
MeSH terms
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism
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Animals
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / genetics
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Aspartic Acid Endopeptidases / metabolism
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Biphenyl Compounds / chemistry
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Biphenyl Compounds / pharmacology*
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Brain / drug effects*
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Brain / metabolism
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Brain / pathology
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Cell Line, Tumor
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Cognition Disorders / drug therapy*
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Cognition Disorders / metabolism
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Cognition Disorders / pathology
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Disease Models, Animal
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Feasibility Studies
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Female
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Humans
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Male
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Maze Learning / drug effects
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Mice
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Mice, Transgenic
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Naphthalenes / chemistry
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Naphthalenes / pharmacology*
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Protease Nexins
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Random Allocation
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism
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Recognition, Psychology / drug effects
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Treatment Outcome
Substances
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APP protein, human
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Biphenyl Compounds
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Enzyme Inhibitors
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Naphthalenes
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Protease Nexins
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Receptors, Cell Surface
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TAK-070
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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Bace1 protein, mouse