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Cited by 168Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and β-amyloid production in Alzheimer’s disease

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Chami, Linda, Checler, Frédéric·2012·Molecular Neurodegeneration
DOI 10.1186/1750-1326-7-52PMC PMC3507664
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Abstract

Alzheimer's disease (AD) is a complex age-related pathology, the etiology of which has not been firmly delineated. Among various histological stigmata, AD-affected brains display several cellular dysfunctions reflecting enhanced oxidative stress, inflammation process and calcium homeostasis disturbance. Most of these alterations are directly or indirectly linked to amyloid β-peptides (Aβ), the production, molecular nature and biophysical properties of which likely conditions the degenerative process. It is particularly noticeable that, in a reverse control process, the above-described cellular dysfunctions alter Aβ peptides levels. β-secretase βAPP-cleaving enzyme 1 (BACE1) is a key molecular contributor of this cross-talk. This enzyme is responsible for the primary cleavage generating the N-terminus of "full length" Aβ peptides and is also transcriptionally induced by several cellular stresses. This review summarizes data linking brain insults to AD-like pathology and documents the key role of BACE1 at the cross-road of a vicious cycle contributing to Aβ production.

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Figures

Figure 1 Oxidative stress mediates Aβ-induced BACE1 transcriptional activation. Aβ peptides trigger oxidative stress by inducing ROS generation and impairing the antioxidant system. Oxidative stress and inflammatory cytokines activates JNK, then its transcription factor AP-1 upregulates BACE1. As BACE1 produces Aβ peptides, a vicious cycle is established. Aβ, amyloid peptide; AP-1, activator protein-1; BACE1, β-secretase βAPP cleaving enzyme 1; JNK, c-Jun N-terminal kinases; ROS, reactive oxygen species.
Figure 1 Oxidative stress mediates Aβ-induced BACE1 transcriptional activation. Aβ peptides trigger oxidative stress by inducing ROS generation and impairing the antioxidant system. Oxidative stress and inflammatory cytokines activates JNK, then its transcription factor AP-1 upregulates BACE1. As BACE1 produces Aβ peptides, a vicious cycle is established. Aβ, amyloid peptide; AP-1, activator protein-1; BACE1, β-secretase βAPP cleaving enzyme 1; JNK, c-Jun N-terminal kinases; ROS, reactive oxygen species.CC BY · PubMed Central
Figure 2 Inflammation mediates Aβ-induced BACE1 transcriptional activation. Aβ peptides are pro-inflammatory. They activate microglia and astrocytes that release inflammatory mediators. Those activate NF-κB, which is also activated by oxidative stress, ischemia or traumatic brain injury. Pathological activation of NF-κB activates BACE1 transcription, thus increasing Aβ peptides levels and feeding a vicious cycle. Aβ, amyloid peptide; BACE1, β-secretase βAPP cleaving enzyme 1; NF-κB, nuclear factor-κB.
Figure 2 Inflammation mediates Aβ-induced BACE1 transcriptional activation. Aβ peptides are pro-inflammatory. They activate microglia and astrocytes that release inflammatory mediators. Those activate NF-κB, which is also activated by oxidative stress, ischemia or traumatic brain injury. Pathological activation of NF-κB activates BACE1 transcription, thus increasing Aβ peptides levels and feeding a vicious cycle. Aβ, amyloid peptide; BACE1, β-secretase βAPP cleaving enzyme 1; NF-κB, nuclear factor-κB.CC BY · PubMed Central
Figure 3 Disturbed calcium homeostasis mediates Aβ-induced BACE1 transcriptional activation. Aβ peptides increase cytoplasmic calcium by at least three mechanisms: stimulation of membrane ion channels or receptors; permeabilization of the membrane; and deregulation of internal calcium channels. Presenilins mutations contribute to the latter. Increased calcium then activates the calpain/cdk5/STAT3 pathway and NFAT1. The transcription factors STAT3 and NFAT1 upregulate BACE1, which then produces more Aβ peptides and a positive feedback mechanism is set up. Aβ, amyloid peptide; BACE1, β-secretase βAPP cleaving enzyme 1; cdk5, cyclin-dependent kinase 5; IP3, inositol 1,4,5-triphosphate; NFAT1, nuclear factor of activated T-cells 1; SERCA, sarco endoplasmic reticulum calcium ATPase; STAT, signal transducer and activator of transcription.
Figure 3 Disturbed calcium homeostasis mediates Aβ-induced BACE1 transcriptional activation. Aβ peptides increase cytoplasmic calcium by at least three mechanisms: stimulation of membrane ion channels or receptors; permeabilization of the membrane; and deregulation of internal calcium channels. Presenilins mutations contribute to the latter. Increased calcium then activates the calpain/cdk5/STAT3 pathway and NFAT1. The transcription factors STAT3 and NFAT1 upregulate BACE1, which then produces more Aβ peptides and a positive feedback mechanism is set up. Aβ, amyloid peptide; BACE1, β-secretase βAPP cleaving enzyme 1; cdk5, cyclin-dependent kinase 5; IP3, inositol 1,4,5-triphosphate; NFAT1, nuclear factor of activated T-cells 1; SERCA, sarco endoplasmic reticulum calcium ATPase; STAT, signal transducer and activator of transcription.CC BY · PubMed Central
Figure 4 Aβ and AGEs activate BACE1 transcription. Aβ peptides activate RAGE. This receptor is also activated by AGEs produced during diabetes mellitus, inflammation or hypoxia. RAGE activation upregulates BACE1 by the activation of the two transcription factors NF-κB and NFAT1. Additionally, AGEs can activate BACE1 by generating oxidative stress. BACE1 contribution to Aβ peptides production then amplifies RAGE activation. Aβ, amyloid peptide; AGE, advanced glycation end products; BACE1, β-secretase βAPP cleaving enzyme 1; NFAT1, nuclear factor of activated T-cells 1; NF-κB, nuclear factor-κB; RAGE, receptor for advanced glycation end products.
Figure 4 Aβ and AGEs activate BACE1 transcription. Aβ peptides activate RAGE. This receptor is also activated by AGEs produced during diabetes mellitus, inflammation or hypoxia. RAGE activation upregulates BACE1 by the activation of the two transcription factors NF-κB and NFAT1. Additionally, AGEs can activate BACE1 by generating oxidative stress. BACE1 contribution to Aβ peptides production then amplifies RAGE activation. Aβ, amyloid peptide; AGE, advanced glycation end products; BACE1, β-secretase βAPP cleaving enzyme 1; NFAT1, nuclear factor of activated T-cells 1; NF-κB, nuclear factor-κB; RAGE, receptor for advanced glycation end products.CC BY · PubMed Central
Figure 5 Traumatic brain injury contributes to Aβ deposition by activating BACE1 transcription. Traumatic brain injury activates BACE1 by inducing oxidative stress and by activating the NF-κB transcription factor. This leads to Aβ deposition. Aβ, amyloid peptide; AGE, advanced glycation end products; BACE1, β-secretase βAPP cleaving enzyme 1; NF-κB, nuclear factor-κB.
Figure 5 Traumatic brain injury contributes to Aβ deposition by activating BACE1 transcription. Traumatic brain injury activates BACE1 by inducing oxidative stress and by activating the NF-κB transcription factor. This leads to Aβ deposition. Aβ, amyloid peptide; AGE, advanced glycation end products; BACE1, β-secretase βAPP cleaving enzyme 1; NF-κB, nuclear factor-κB.CC BY · PubMed Central
Figure 6 Hypoxia contributes to Aβ deposition by activating BACE1 transcription. Hypoxia activates BACE1 by three distinct mechanisms: generation of oxidative stress and the subsequent activation of the JNK pathway; activation of HIF-1 transcription factor which activates BACE1 promoter directly or indirectly through the activation of NF-κB and RAGE; activation of calpain and cdk5 resulting from increased calcium concentrations. By activating BACE1 transcription, hypoxia thus leads to Aβ deposition. Aβ, amyloid peptide; AGE, advanced glycation end products; BACE1, β-secretase βAPP cleaving enzyme 1; cdk5, cyclin-dependent kinase 5; HIF-1, hypoxia-inducible factor 1; JNK, c-Jun N-terminal kinases; NF-κB, nuclear factor-κB; RAGE, receptor for advanced glycation end products.
Figure 6 Hypoxia contributes to Aβ deposition by activating BACE1 transcription. Hypoxia activates BACE1 by three distinct mechanisms: generation of oxidative stress and the subsequent activation of the JNK pathway; activation of HIF-1 transcription factor which activates BACE1 promoter directly or indirectly through the activation of NF-κB and RAGE; activation of calpain and cdk5 resulting from increased calcium concentrations. By activating BACE1 transcription, hypoxia thus leads to Aβ deposition. Aβ, amyloid peptide; AGE, advanced glycation end products; BACE1, β-secretase βAPP cleaving enzyme 1; cdk5, cyclin-dependent kinase 5; HIF-1, hypoxia-inducible factor 1; JNK, c-Jun N-terminal kinases; NF-κB, nuclear factor-κB; RAGE, receptor for advanced glycation end products.CC BY · PubMed Central
Figure 7 Cellular stress, BACE1 and Aβ production are involved in a toxic vicious cycle in AD. Various cellular dysfunctions including oxidative stress, inflammation and calcium homeostasis disturbance occur in AD-affected brains. These alterations activate the transcription of the stress-induced β-secretase BACE1 that contributes to Aβ production. Once yielded at supra-physiological levels, Aβ induces cellular stresses that, in turn activate BACE1, therefore setting up a vicious cycle. Such self-maintained toxicity can lead to cellular cell death. Brain insults like hypoxia and traumatic brain injury contribute to this scheme by inducing cellular stress.
Figure 7 Cellular stress, BACE1 and Aβ production are involved in a toxic vicious cycle in AD. Various cellular dysfunctions including oxidative stress, inflammation and calcium homeostasis disturbance occur in AD-affected brains. These alterations activate the transcription of the stress-induced β-secretase BACE1 that contributes to Aβ production. Once yielded at supra-physiological levels, Aβ induces cellular stresses that, in turn activate BACE1, therefore setting up a vicious cycle. Such self-maintained toxicity can lead to cellular cell death. Brain insults like hypoxia and traumatic brain injury contribute to this scheme by inducing cellular stress.CC BY · PubMed Central

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Cites

Show all 217 references

Research works printed but not linked: 5

  1. Querfurth HW LaFerla FM Alzheimer's disease N Engl J Med 2010 362 329 344 20107219
  2. Chen CH Zhou W Liu S Deng Y Cai F Tone M Tone Y Tong Y Song W Increased NF-kappaB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer's disease Int J Neuropsychopharmacol 2011 1 14 21329555
  3. Buggia-Prevot V Sevalle J Rossner S Checler F NFkappaB-dependent control of BACE1 promoter transactivation by Abeta42 J Biol Chem 2008 283 10037 10047 18263584
  4. Guglielmotto M Monteleone D Giliberto L Fornaro M Borghi R Tamagno E Tabaton M Amyloid-beta activates the expression of BACE1 through the JNK pathway J Alzheimers Dis 2011 27 871 883 21897006
  5. Guglielmotto M Aragno M Tamagno E Vercellinatto I Visentin S Medana C Catalano MG Smith MA Perry G Danni O AGEs/RAGE complex upregulates BACE1 via NF-kappaB pathway activation Neurobiol Aging 2012 33 196.e13 27 20638753

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Metadata

Authors
Chami, L., & Checler, F.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
Checler, Frédéric
ORCID
Checler, Frédéric
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2012
Volume
7
Issue
1
Pages
52
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/1750-1326-7-52
PMC
PMC3507664
OpenAlex
W2111994753
Cited by
168
References
217
Citations by year
2026: 11 · 2025: 8 · 2024: 12 · 2023: 12 · 2022: 8 · 2021: 8 · 2020: 8 · 2019: 16 · 2018: 15 · 2017: 13 · 2016: 14 · 2015: 15 · 2014: 22 · 2013: 5
FWCI
1.46
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease
  • Fondation pour la Recherche Médicale
  • Ministère de l'Enseignement Supérieur et de la Recherche
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, BACE1, beta-secretase, amyloid-beta, oxidative stress, cellular stress, vicious circle, inflammation, calcium homeostasis, APP cleavage, neurodegeneration
MeSH terms
Alzheimer Disease, Animals, Humans, Stress, Physiological, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid Precursor Protein Secretases

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