Amyloid precursor protein‐mediated mitochondrial regulation and Alzheimer's disease
Open accessAbstract
Despite clear evidence of a neuroprotective physiological role of amyloid precursor protein (APP) and its non‐amyloidogenic processing products, APP has been investigated mainly in animal and cellular models of amyloid pathology in the context of Alzheimer's disease. The rare familial mutations in APP and presenilin‐1/2, which sometimes drive increased amyloid β (Aβ) production, may have unduly influenced Alzheimer's disease research. APP and its cleavage products play important roles in cellular and mitochondrial metabolism, but many studies focus solely on Aβ. Mitochondrial bioenergetic metabolism is essential for neuronal function, maintenance and survival, and multiple reports indicate mitochondrial abnormalities in patients with Alzheimer's disease. In this review, we focus on mitochondrial abnormalities reported in sporadic Alzheimer's disease patients and the role of full‐length APP and its non‐amyloidogenic fragments, particularly soluble APPα, on mitochondrial bioenergetic metabolism. We do not review the plethora of animal and in vitro studies using mutant APP/presenilin constructs or experiments using exogenous Aβ. In doing so, we aim to invigorate research and discussion around non‐amyloidogenic APP processing products and the mechanisms linking mitochondria and complex neurodegenerative disorders such as sporadic Alzheimer's disease. Linked Articles: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc
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The non-amyloidogenic pathway, mediated by α-secretase primarily ADAM10 and ADAM17, precludes Aβ generation by cleaving APP within the Aβ sequence and releasing sAPPα, which has neurotrophic and neuroprotective functions.
“In contrast, the non-amyloidogenic pathway, mediated by α-secretase, primarily A Disintegrin and metalloproteinase domain-containing protein 10 and 17 (ADAM10 and ADAM17), precludes Aβ generation by cleaving APP within the Aβ sequence and releasing soluble APP alpha (sAPPα), a fragment with neurotrophic and neuroprotective functions [33].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [33]
The Introduction (page unavailable) identifies ADAM10 as the predominant α-secretase, says this pathway releases sAPPα, and explains that cleavage within the Aβ sequence prevents Aβ formation. The section on sAPPα-mediated protection describes neuroprotective effects, and the APP and mitochondrial metabolism section calls sAPPα neurotrophic. Our copy does not identify ADAM17 as a primary α-secretase, so that part of the claim is unsupported. (LLM, conf=0.88)
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- Authors
- Lopez Sanchez, M. I. G., van Wijngaarden, P., & Trounce, I. A.
- Affiliations
- Ophthalmology, Department of Surgery University of Melbourne Melbourne VIC Australia
- The University of Melbourne (AU)
- Corresponding author
- Trounce, Ian A
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2018-12-18
- Volume
- 176
- Issue
- 18
- Pages
- 3464-3474
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC6715589
- OpenAlex
- W2901590244
- Cited by
- 45
- References
- 16
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 3 · 2023: 4 · 2022: 8 · 2021: 5 · 2020: 7 · 2019: 5
- FWCI
- 0.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- BrightFocus Foundation (Thomas R. Lee award (G2009020), G2009020)
- Judith Jane Mason and Harold Stannett Williams Memorial Foundation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid precursor protein, Alzheimer's disease, mitochondrial bioenergetics, mitochondrial dysfunction, soluble APP alpha, sporadic Alzheimer's disease, familial Alzheimer's disease mutations, presenilin, amyloid-beta, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Energy Metabolism, Humans, Mitochondria, Amyloid beta-Protein Precursor
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