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PMID: 16354928 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 25 ·No. 50 ·2005-12-14 ·Pages 11693-709

Laird FM, Cai H, Savonenko AV, Farah MH, He K, Melnikova T, Wen H, Chiang HC, Xu G, Koliatsos VE, Borchelt DR, Price DL, Lee HK, Wong PC

Abstract

A transmembrane aspartyl protease termed beta-site APP cleavage enzyme 1 (BACE1) that cleaves the amyloid-beta precursor protein (APP), which is abundant in neurons, is required for the generation of amyloid-beta (Abeta) 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 Abeta amyloidogenesis. The physiologically high levels of BACE1 activity coupled with low levels of BACE2 and alpha-secretase anti-amyloidogenic activities in neurons is a major contributor to the accumulation of Abeta in the CNS, whereas other organs are spared. Significantly, deletion of BACE1 in APPswe;PS1DeltaE9 mice prevents both Abeta deposition and age-associated cognitive abnormalities that occur in this model of Abeta amyloidosis. Moreover, Abeta 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;PS1DeltaE9 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 Abeta amyloidosis in AD.

MeSH Terms
Amyloid Precursor Protein Secretases Amyloid beta-Protein Precursor/biosynthesis,genetics Animals Aspartic Acid Endopeptidases Brain/pathology Cognition/physiology Emotions/physiology Endopeptidases/deficiency,genetics,physiology Female Humans Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Protein Processing, Post-Translational/physiology Synaptic Transmission/physiology
Chemicals
Amyloid beta-Protein Precursor Amyloid Precursor Protein Secretases Endopeptidases Aspartic Acid Endopeptidases BACE2 protein, human BACE1 protein, human Bace1 protein, mouse
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Laird Fiona M
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Cai Huaibin
Savonenko Alena V
Farah Mohamed H
He Kaiwen
Melnikova Tatyana
Wen Hongjin
Chiang Hsueh-Cheng
Xu Guilian
Koliatsos Vassilis E
Borchelt David R
Price Donald L
Lee Hey-Kyoung
Wong Philip C
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.2766-05.2005
Published
2005-12-14
Pages
11693-709
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC2564291
Subset
IM
Grants
NINDS NIH HHS · R01 NS041438 · United States
NIA NIH HHS · AG02556 · United States
NINDS NIH HHS · P01 NS047308 · United States
Intramural NIH HHS · Z99 AG999999 · United States
NINDS NIH HHS · R01 NS45150 · United States
NINDS NIH HHS · R01 NS41438 · United States
NINDS NIH HHS · R01 NS045150 · United States
NIA NIH HHS · P50 AG05146 · United States
Intramural NIH HHS · Z01 AG000959-04 · United States
NIA NIH HHS · P50 AG005146 · United States
External Links
PubMed source DOI: 10.1523/JNEUROSCI.2766-05.2005 PMC Full Text View journal details
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