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The transmembrane domain of the amyloid precursor protein is required for antiamyloidogenic processing by α-secretase ADAM10

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Hitschler, Lisa, Lang, Thorsten·2022·Journal of Biological Chemistry
DOI 10.1016/j.jbc.2022.101911PMC PMC9127328
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Abstract

Neurotoxic amyloid β-peptides are thought to be a causative agent of Alzheimer's disease in humans. The production of amyloid β-peptides from amyloid precursor protein (APP) could be diminished by enhancing α-processing; however, the physical interactions between APP and α-secretases are not well understood. In this study, we employed super-resolution light microscopy to examine in cell-free plasma membranes the abundance and association of APP and α-secretases ADAM10 (a disintegrin and metalloproteinase) and ADAM17. We found that both secretase molecules localize similarly closely to APP (within ≤50 nm). However, when cross-linking APP with antibodies directed against the GFP tag of APP, in confocal microscopy, we observed that only ADAM10 coaggregated with APP. Furthermore, we mapped the involved protein domain by using APP variants with an exchanged transmembrane segment or lacking cytoplasmic/extracellular domains. We identified that the transmembrane domain of APP is required for association with α-secretases and, as analyzed by Western blot, for α-processing. We propose that the transmembrane domain of APP interacts either directly or indirectly with ADAM10, but not with ADAM17, explaining the dominant role of ADAM10 in α-processing of APP. Further understanding of this interaction may facilitate the development of a therapeutic strategy based on promoting APP cleavage by α-secretases.

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  • α-Secretase activity can be enhanced by PACAP, protein kinase C activators, and possibly environmental modulators.

    “The regulation of α-secretase activity remains incompletely understood, although it can be enhanced by factors such as pituitary adenylate cyclase-activating peptide (PACAP), protein kinase C activators, and possibly environmental modulators [34].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [34]

    The indexed passage labeled Abstract says ADAMs are regulated through protein kinase C and reports phorbol ester–stimulated α-cleavage; it also says the molecular details are not yet understood. The Discussion section on α-secretases as a treatment target discusses enhancing α-processing. Neither section supports PACAP or environmental modulators as enhancers of α-secretase activity. (LLM, conf=0.86)

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Authors
Hitschler, L., & Lang, T.
Affiliations
University of Bonn (DE)
Corresponding author
Lang, Thorsten
ORCID
Lang, Thorsten
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2022-06
Volume
298
Issue
6
Pages
101911
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/j.jbc.2022.101911
PMC
PMC9127328
OpenAlex
W4223480264
Cited by
11
References
1
Citations by year
2026: 1 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 1
FWCI
1.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Deutsche Forschungsgemeinschaft
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
amyloid precursor protein, ADAM10, ADAM17, alpha-secretase, transmembrane domain, amyloid-beta, Alzheimer's disease, plasma membrane, super-resolution microscopy
MeSH terms
ADAM10 Protein, ADAM17 Protein, Protein Domains, Alzheimer Disease, Humans, Membrane Proteins, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Amyloid Precursor Protein Secretases

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