The Journal of Neuroscience, December 14, 2005, 25(50):11693-11709; doi:10.1523/JNEUROSCI.2766-05.2005
Previous Article | Next Article 
Neurobiology of Disease
BACE1, a Major Determinant of Selective Vulnerability of the Brain to Amyloid-
Amyloidogenesis, is Essential for Cognitive, Emotional, and Synaptic Functions
Fiona M. Laird,1 *
Huaibin Cai,5 *
Alena V. Savonenko,1,2 *
Mohamed H. Farah,1 *
Kaiwen He,6
Tatyana Melnikova,1,2
Hongjin Wen,1
Hsueh-Cheng Chiang,1
Guilian Xu,1
Vassilis E. Koliatsos,1,2,3,4
David R. Borchelt,1,3
Donald L. Price,1,2,3
Hey-Kyoung Lee,6 and
Philip C. Wong1,3
Departments of 1Pathology, 2Neurology, 3Neuroscience, and 4Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, 5Laboratory of Neurogenetics, National Institutes of Health, Bethesda, Maryland 20892, and 6Department of Biology, University of Maryland, College Park, Maryland 20742
A transmembrane aspartyl protease termed 
-site APP cleavage enzyme 1 (BACE1) that cleaves the amyloid- precursor protein (APP), which is abundant in neurons, is required for the generation of amyloid- (A) peptides implicated in the pathogenesis of Alzheimer's disease (AD). We now demonstrate that BACE1, enriched in neurons of the CNS, is a major determinant that predisposes the brain to A amyloidogenesis. The physiologically high levels of BACE1 activity coupled with low levels of BACE2 and 
-secretase anti-amyloidogenic activities in neurons is a major contributor to the accumulation of A in the CNS, whereas other organs are spared. Significantly, deletion of BACE1 in APPswe;PS1
E9 mice prevents both A deposition and age-associated cognitive abnormalities that occur in this model of A amyloidosis. Moreover, A deposits are sensitive to BACE1 dosage and can be efficiently cleared from the CNS when BACE1 is silenced. However, BACE1 null mice manifest alterations in hippocampal synaptic plasticity as well as in performance on tests of cognition and emotion. Importantly, memory deficits but not emotional alterations in BACE1–/– mice are prevented by coexpressing APPswe;PS1E9 transgenes, indicating that other potential substrates of BACE1 may affect neural circuits related to emotion. Our results establish BACE1 and APP processing pathways as critical for cognitive, emotional, and synaptic functions, and future studies should be alert to potential mechanism-based side effects that may occur with BACE1 inhibitors designed to ameliorate A amyloidosis in AD.
Key words: BACE1 null mice; selective vulnerability; A amyloidosis; Alzheimer's; cognition; synaptic plasticity; RNAi
Received April 4, 2005;
revised October 10, 2005;
accepted November 3, 2005.
