BACE1 Deficiency Rescues Memory Deficits and Cholinergic Dysfunction in a Mouse Model of Alzheimer's Disease

Masuo Ohno, Evgeny A. Sametsky, Linda H. Younkin, Holly Oakley, Steven G. Younkin, Martin Citron, Robert Vassar, John F. Disterhoft

Research output: Contribution to journalArticle

435 Scopus citations

Abstract

β-site APP cleaving enzyme 1 (BACE1) is the β-secretase enzyme required for generating pathogenic β-amyloid (Aβ) peptides in Alzheimer's disease (AD). BACE1 knockout mice lack Aβ and are phenotypically normal, suggesting that therapeutic inhibition of BACE1 may be free of mechanism-based side effects. However, direct evidence that BACE1 inhibition would improve cognition is lacking. Here we show that BACE1 null mice engineered to overexpress human APP (BACE1-/-·Tg2576 +) are rescued from Aβ-dependent hippocampal memory deficits. Moreover, impaired hippocampal cholinergic regulation of neuronal excitability found in the Tg2576 AD model is ameliorated in BACE1-/-·Tg2576+ bigenic mice. The behavioral and electrophysiological rescue of deficits in BACE1-/-·Tg2576+ mice is correlated with a dramatic reduction of cerebral Aβ40 and Aβ42 levels and occurs before amyloid deposition in Tg2576 mice. Our gene-based approach demonstrates that lower Aβ levels are beneficial for AD-associated memory impairments, validating BACE1 as a therapeutic target for AD.

Original languageEnglish (US)
Pages (from-to)27-33
Number of pages7
JournalNeuron
Volume41
Issue number1
DOIs
StatePublished - Jan 8 2004

ASJC Scopus subject areas

  • Neuroscience(all)

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    Ohno, M., Sametsky, E. A., Younkin, L. H., Oakley, H., Younkin, S. G., Citron, M., Vassar, R., & Disterhoft, J. F. (2004). BACE1 Deficiency Rescues Memory Deficits and Cholinergic Dysfunction in a Mouse Model of Alzheimer's Disease. Neuron, 41(1), 27-33. https://doi.org/10.1016/S0896-6273(03)00810-9