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BACE1, a Major Determinant of Selective Vulnerability of the Brain to Amyloid-β Amyloidogenesis, is Essential for Cognitive, Emotional, and Synaptic Functions

Authors :
Philip C. Wong
David R. Borchelt
Hsueh Cheng Chiang
Vassilis E. Koliatsos
Donald L. Price
Hongjin Wen
Hey Kyoung Lee
Kaiwen He
Fiona M. Laird
Alena Savonenko
Tatyana Melnikova
Guilian Xu
Huaibin Cai
Mohamed H. Farah
Source :
The Journal of Neuroscience. 25:11693-11709
Publication Year :
2005
Publisher :
Society for Neuroscience, 2005.

Abstract

A transmembrane aspartyl protease termed β-site APP cleavage enzyme 1 (BACE1) that cleaves the amyloid-β precursor protein (APP), which is abundant in neurons, is required for the generation of amyloid-β (Aβ) 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 Aβ amyloidogenesis. The physiologically high levels of BACE1 activity coupled with low levels of BACE2 and α-secretase anti-amyloidogenic activities in neurons is a major contributor to the accumulation of Aβ in the CNS, whereas other organs are spared. Significantly, deletion ofBACE1inAPPswe;PS1ΔE9mice prevents both Aβ deposition and age-associated cognitive abnormalities that occur in this model of Aβ amyloidosis. Moreover, Aβ deposits are sensitive toBACE1dosage and can be efficiently cleared from the CNS whenBACE1is silenced. However,BACE1null 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 inBACE1–/–mice are prevented by coexpressingAPPswe;PS1ΔE9transgenes, 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 Aβ amyloidosis in AD.

Details

ISSN :
15292401 and 02706474
Volume :
25
Database :
OpenAIRE
Journal :
The Journal of Neuroscience
Accession number :
edsair.doi.dedup.....4f1efccdf48011d5690396b46366ddc4
Full Text :
https://doi.org/10.1523/jneurosci.2766-05.2005