BACE1 Deficiency Rescues Memory Deficits and Cholinergic Dysfunction in a Mouse Model of Alzheimer's Disease
2004; Cell Press; Volume: 41; Issue: 1 Linguagem: Inglês
10.1016/s0896-6273(03)00810-9
ISSN1097-4199
AutoresMasuo Ohno, Evgeny A. Sametsky, Linda H. Younkin, Holly D. Oakley, Steven G. Younkin, Martin Citron, Robert Vassar, John F. Disterhoft,
Tópico(s)Computational Drug Discovery Methods
ResumoAbstract 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.
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