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Cited by 73Alzheimer's disease research and treatmentsProtease and Inhibitor MechanismsDementia and Cognitive Impairment Research

Cathepsin D regulates cerebral Aβ42/40 ratios via differential degradation of Aβ42 and Aβ40

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Suire, Caitlin N., Abdul-Hay, Samer O., Sahara, Tomoko, Kang, Dongcheul, Brizuela, Monica K., Saftig, Paul, Dickson, Dennis W., Rosenberry, Terrone L. +1 more·2020·Alzheimer's Research & Therapy
DOI 10.1186/s13195-020-00649-8PMC PMC7339583
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Abstract

Background: Cathepsin D (CatD) is a lysosomal protease that degrades both the amyloid β-protein (Aβ) and the microtubule-associated protein, tau, and has been genetically linked to late-onset Alzheimer disease (AD). Here, we sought to examine the consequences of genetic deletion of CatD on Aβ proteostasis in vivo and to more completely characterize the degradation of Aβ42 and Aβ40 by CatD. Methods: We quantified Aβ degradation rates and levels of endogenous Aβ42 and Aβ40 in the brains of CatD-null (CatD-KO), heterozygous null (CatD-HET), and wild-type (WT) control mice. CatD-KO mice die by ~ 4 weeks of age, so tissues from younger mice, as well as embryonic neuronal cultures, were investigated. Enzymological assays and surface plasmon resonance were employed to quantify the kinetic parameters ( K M , k cat ) of CatD-mediated degradation of monomeric human Aβ42 vs. Aβ40, and the degradation of aggregated Aβ42 species was also characterized. Competitive inhibition assays were used to interrogate the relative inhibition of full-length human and mouse Aβ42 and Aβ40, as well as corresponding p3 fragments. Results: Genetic deletion of CatD resulted in 3- to 4-fold increases in insoluble, endogenous cerebral Aβ42 and Aβ40, exceeding the increases produced by deletion of an insulin-degrading enzyme, neprilysin or both, together with readily detectable intralysosomal deposits of endogenous Aβ42—all by 3 weeks of age. Quite significantly, CatD-KO mice exhibited ~ 30% increases in Aβ42/40 ratios, comparable to those induced by presenilin mutations. Mechanistically, the perturbed Aβ42/40 ratios were attributable to pronounced differences in the kinetics of degradation of Aβ42 vis-à-vis Aβ40. Specifically, Aβ42 shows a low-nanomolar affinity for CatD, along with an exceptionally slow turnover rate that, together, renders Aβ42 a highly potent competitive inhibitor of CatD. Notably, the marked differences in the processing of Aβ42 vs. Aβ40 also extend to p3 fragments ending at positions 42 vs. 40. Conclusions: Our findings identify CatD as the principal intracellular Aβ-degrading protease identified to date, one that regulates Aβ42/40 ratios via differential degradation of Aβ42 vs. Aβ40. The finding that Aβ42 is a potent competitive inhibitor of CatD suggests a possible mechanistic link between elevations in Aβ42 and downstream pathological sequelae in AD.

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  • At least five other PD-associated genes (LRRK2, UCHL2, VCP35, DJ-1, and SNCA) affect CMA.

    “At least five other genes that are associated with PD (but not LSDs) also affect CMA: LRRK2, UCHL2, VCP35, DJ-1, and SNCA, which encodes alpha-synuclein.149–153”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [150]

    The Discussion addresses cathepsin D and amyloid-β in Alzheimer’s disease, while the References include work on lysosomal processing; neither addresses whether the five named Parkinson’s disease genes affect CMA. Searches for the gene names and for chaperone-mediated autophagy found no passage supporting the attributed claim. (LLM, conf=0.76)

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Authors
Suire, C. N., Abdul-Hay, S. O., Sahara, T., Kang, D., Brizuela, M. K., Saftig, P., Dickson, D. W., Rosenberry, T. L., & Leissring, M. A.
Affiliations
  • University of California, Irvine (US)
  • Mayo Clinic in Florida (US)
Corresponding author
Leissring, Malcolm A.
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2020-07-06
Volume
12
Issue
1
Pages
80-80
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-020-00649-8
PMC
PMC7339583
OpenAlex
W3039837585
Cited by
73
References
8
Citations by year
2026: 7 · 2025: 17 · 2024: 15 · 2023: 20 · 2022: 4 · 2021: 9 · 2020: 1
FWCI
5.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • National Institute on Aging (AG052718)
  • National Institute of General Medical Sciences (GM115617)
  • American Health Assistance Foundation (A2009-013)
  • Alzheimer's Association (IIRG-07-59693)
  • Deutsche Forschungsgemeinschaft (SFB877)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
cathepsin D, amyloid-beta, Aβ42/Aβ40 ratio, amyloid beta degradation, lysosomal proteolysis, Alzheimer's disease, protease kinetics, competitive inhibition, tau protein, neprilysin, insulin-degrading enzyme, presenilin mutations
MeSH terms
Alzheimer Disease, Animals, Cathepsin D, Peptide Fragments, Amyloid beta-Peptides, Mice

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