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

Fiona M. Laird, Huaibin Cai, Alena Savonenko, Mohamed H Farah, Kaiwen He, Tatyana Melnikova, Hongjin Wen, Hsueh Cheng Chiang, Guilian Xu, Vassilis El Koliatsos, David R. Borchelt, Donald L. Price, Hey-Kyoung Lee, Philip Chun Wong

Research output: Contribution to journalArticle

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 of BACE1 in APPswe;PS1ΔE9 mice prevents both Aβ deposition and age-associated cognitive abnormalities that occur in this model of Aβ amyloidosis. Moreover, Aβ 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;PS1ΔE9 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 Aβ amyloidosis in AD.

Original languageEnglish (US)
Pages (from-to)11693-11709
Number of pages17
JournalJournal of Neuroscience
Volume25
Issue number50
DOIs
StatePublished - Dec 14 2005

Fingerprint

Amyloid beta-Protein Precursor
Amyloid
Amyloidosis
Neurons
Alzheimer Disease
Brain
Emotions
Aspartic Acid Proteases
Amyloid Precursor Protein Secretases
Neuronal Plasticity
Critical Pathways
Memory Disorders
Transgenes
Cognition
Peptides
Enzymes

Keywords

  • Aβ amyloidosis
  • Alzheimer's
  • BACE1 null mice
  • Cognition
  • RNAi
  • Selective vulnerability
  • Synaptic plasticity

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

BACE1, a major determinant of selective vulnerability of the brain to amyloid-β amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. / Laird, Fiona M.; Cai, Huaibin; Savonenko, Alena; Farah, Mohamed H; He, Kaiwen; Melnikova, Tatyana; Wen, Hongjin; Chiang, Hsueh Cheng; Xu, Guilian; Koliatsos, Vassilis El; Borchelt, David R.; Price, Donald L.; Lee, Hey-Kyoung; Wong, Philip Chun.

In: Journal of Neuroscience, Vol. 25, No. 50, 14.12.2005, p. 11693-11709.

Research output: Contribution to journalArticle

Laird, Fiona M. ; Cai, Huaibin ; Savonenko, Alena ; Farah, Mohamed H ; He, Kaiwen ; Melnikova, Tatyana ; Wen, Hongjin ; Chiang, Hsueh Cheng ; Xu, Guilian ; Koliatsos, Vassilis El ; Borchelt, David R. ; Price, Donald L. ; Lee, Hey-Kyoung ; Wong, Philip Chun. / BACE1, a major determinant of selective vulnerability of the brain to amyloid-β amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 50. pp. 11693-11709.
@article{3fdf604e4aeb4f158a3a62ed75dc7331,
title = "BACE1, a major determinant of selective vulnerability of the brain to amyloid-β amyloidogenesis, is essential for cognitive, emotional, and synaptic functions",
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 of BACE1 in APPswe;PS1ΔE9 mice prevents both Aβ deposition and age-associated cognitive abnormalities that occur in this model of Aβ amyloidosis. Moreover, Aβ 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;PS1ΔE9 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 Aβ amyloidosis in AD.",
keywords = "Aβ amyloidosis, Alzheimer's, BACE1 null mice, Cognition, RNAi, Selective vulnerability, Synaptic plasticity",
author = "Laird, {Fiona M.} and Huaibin Cai and Alena Savonenko and Farah, {Mohamed H} and Kaiwen He and Tatyana Melnikova and Hongjin Wen and Chiang, {Hsueh Cheng} and Guilian Xu and Koliatsos, {Vassilis El} and Borchelt, {David R.} and Price, {Donald L.} and Hey-Kyoung Lee and Wong, {Philip Chun}",
year = "2005",
month = "12",
day = "14",
doi = "10.1523/JNEUROSCI.2766-05.2005",
language = "English (US)",
volume = "25",
pages = "11693--11709",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "50",

}

TY - JOUR

T1 - BACE1, a major determinant of selective vulnerability of the brain to amyloid-β amyloidogenesis, is essential for cognitive, emotional, and synaptic functions

AU - Laird, Fiona M.

AU - Cai, Huaibin

AU - Savonenko, Alena

AU - Farah, Mohamed H

AU - He, Kaiwen

AU - Melnikova, Tatyana

AU - Wen, Hongjin

AU - Chiang, Hsueh Cheng

AU - Xu, Guilian

AU - Koliatsos, Vassilis El

AU - Borchelt, David R.

AU - Price, Donald L.

AU - Lee, Hey-Kyoung

AU - Wong, Philip Chun

PY - 2005/12/14

Y1 - 2005/12/14

N2 - 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 of BACE1 in APPswe;PS1ΔE9 mice prevents both Aβ deposition and age-associated cognitive abnormalities that occur in this model of Aβ amyloidosis. Moreover, Aβ 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;PS1ΔE9 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 Aβ amyloidosis in AD.

AB - 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 of BACE1 in APPswe;PS1ΔE9 mice prevents both Aβ deposition and age-associated cognitive abnormalities that occur in this model of Aβ amyloidosis. Moreover, Aβ 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;PS1ΔE9 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 Aβ amyloidosis in AD.

KW - Aβ amyloidosis

KW - Alzheimer's

KW - BACE1 null mice

KW - Cognition

KW - RNAi

KW - Selective vulnerability

KW - Synaptic plasticity

UR - http://www.scopus.com/inward/record.url?scp=30444440132&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=30444440132&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.2766-05.2005

DO - 10.1523/JNEUROSCI.2766-05.2005

M3 - Article

C2 - 16354928

AN - SCOPUS:30444440132

VL - 25

SP - 11693

EP - 11709

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 50

ER -