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Cited by 799Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

The secretases: enzymes with therapeutic potential in Alzheimer disease

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De Strooper, Bart, Vassar, Robert, Golde, Todd·2010·Nature Reviews Neurology
DOI 10.1038/nrneurol.2009.218PMC PMC2879045
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Abstract

The amyloid hypothesis has yielded a series of well-validated candidate drug targets with potential for the treatment of Alzheimer disease (AD). Three proteases that are involved in the processing of amyloid precursor protein-alpha-secretase, beta-secretase and gamma-secretase-are of particular interest as they are central to the generation and modulation of amyloid-beta peptide and can be targeted by small compounds in vitro and in vivo. Given that these proteases also fulfill other important biological roles, inhibiting their activity will clearly be inherently associated with mechanism-based toxicity. Carefully determining a suitable therapeutic window and optimizing the selectivity of the drug treatments towards amyloid precursor protein processing might be ways of overcoming this potential complication. Secretase inhibitors are likely to be the first small-molecule therapies aimed at AD modification that will be fully tested in the clinic. Success or failure of these first-generation AD therapies will have enormous consequences for further drug development efforts for AD and possibly other neurodegenerative conditions.

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  • BACE1 has a rate-limiting role in Aβ generation from APP.

    “Given the rate-limiting role of BACE1 in Aβ generation from APP, strategies to lower cerebral Aβ levels by inhibiting BACE1 have been extensively pursued as AD therapeutics (De Strooper et al. 2010).”

    From miR‐186 is decreased in aged brain and suppresses <scp>BACE</scp>1 expression (2016) · cites this paper as De Strooper et al. 2010

    In β-Secretase > Biological activity (page unavailable), the review says BACE1 is the main, if not the only, β-secretase in the brain and that mice lacking BACE1 have no cerebral Aβ. β-Secretase > Drug development (page unavailable) describes BACE1 inhibitors developed to lower cerebral Aβ. These passages support BACE1’s importance and the therapeutic strategy, but do not establish that its action is specifically rate-limiting. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • APP located at the cell surface is more likely to undergo α-secretase cleavage to produce sAPPα, thereby reducing Aβ production.

    “Thus, APP located at the cell surface is more likely to undergo α-secretase cleavage to produce sAPPα, thereby reducing Aβ production.”

    From Mercaptoacetamide-based class II HDAC inhibitor lowers Aβ levels and improves learning and memory in a mouse model of Alzheimer's disease (2013) · cites this paper as De Strooper, et al., 2010

    The α-Secretases, Biological activity section says α-secretase cleavage produces soluble APPsα and can reduce Aβ production, although the latter finding has not been universally replicated. It does not say that APP at the cell surface is more likely to undergo this cleavage than APP elsewhere. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
De Strooper, B., Vassar, R., & Golde, T.
Affiliations
  • Northwestern University (US)
  • Mayo Clinic (US)
ORCID
Venue
Nature Reviews Neurology
Publisher
Springer Science and Business Media LLC
Published
2010-02
Volume
6
Issue
2
Pages
99-107
ISSN
  • 1759-4758 (ISSN-L)
  • 1759-4766
DOI
10.1038/nrneurol.2009.218
PMC
PMC2879045
OpenAlex
W2068042361
Cited by
799
References
9
Citations by year
2026: 15 · 2025: 24 · 2024: 35 · 2023: 43 · 2022: 43 · 2021: 50 · 2020: 58 · 2019: 48 · 2018: 43 · 2017: 47 · 2016: 70 · 2015: 65 · 2014: 63 · 2013: 59 · 2012: 63
FWCI
6.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Lirias (submittedVersion)
Funders
National Institute on Aging (AG25531, R01AG030142, R01AG022560, P01AG025531, P01AG021184)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
Alzheimer's disease, secretases, amyloid precursor protein, amyloid-beta, alpha-secretase, beta-secretase, gamma-secretase, secretase inhibitors, amyloid hypothesis, therapeutic target, enzyme selectivity, small molecule drugs, neurodegenerative diseases
MeSH terms
Alzheimer Disease, Animals, Enzyme Inhibitors, Humans, Amyloid beta-Protein Precursor, Amyloid Precursor Protein Secretases

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