The effects of perturbed energy metabolism on the processing of amyloid precursor protein in PC12 cells
Abstract
The mismetabolism of amyloid precursor protein (APP), favouring the production of A beta, is considered to be central to the pathogenesis of Alzheimer's disease (AD). However it remains to be established whether the causative factor is the reported toxicity of A beta or reduced production of secretory derivatives of APP which may have trophic or neuroprotective properties. One possible contributory factor to an imbalance in APP metabolism is the impaired cellular energy availability described in AD. The aim of this study was to investigate processing of APP-like proteins following inhibition of oxidative energy metabolism in PC12 cells. Under these conditions, intracellular and secreted APP-like proteins were significantly reduced. Treatment of energy perturbed cells with the lysosomotropic agent chloroquine restored intracellular concentrations of APP-like proteins to the control range, while the secretion was completely restored by activation of protein kinase C. These findings raise the possibility that energy related metabolic stress may lead to altered metabolism of APP-like proteins favouring a potentially amyloidogenic pathway. Furthermore, the observation that activation of PKC is able to overcome this potentially pathogenic process has important implications for treatment of AD with the current generation of cholinomimetic drugs, suggesting that such drugs may slow disease progression as well as improve cognitive dysfunction.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mitochondria directly influence other AD-associated pathologies, particularly APP and Aβ homeostasis.
“Data also argue mitochondria directly influence other AD-associated pathologies, and particularly APP and Aβ homeostasis.”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [49]
Whether Aβ changes precede either age-related or AD-related brain bioenergetic changes is less clear-cut.
“Whether Aβ changes precede either age-related or AD-related brain bioenergetic changes is less clear-cut, especially since abundant data from human and cell-based studies either suggest or demonstrate bioenergetic factors regulate both APP processing and Aβ production [95–100].”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [98]
Abundant data from human and cell-based studies either suggest or demonstrate bioenergetic factors regulate both APP processing and Aβ production.
“Whether Aβ changes precede either age-related or AD-related brain bioenergetic changes is less clear-cut, especially since abundant data from human and cell-based studies either suggest or demonstrate bioenergetic factors regulate both APP processing and Aβ production [95–100].”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [98]
COX inhibition and ATP depletion both reduced non-amyloidogenic, α secretase-mediated APP processing in cell culture experiments.
“This was directly demonstrated in cell culture experiments in which COX inhibition and ATP depletion both reduced non-amyloidogenic, α secretase-mediated APP processing [95, 96, 98].”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [98]
Bioenergetic metabolism affects APP processing and Aβ production.
“Bioenergetic metabolism certainly affects APP processing and Aβ production.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [98]
The citation lists haven’t been fetched yet
References 49 · Cited by 62
- Authors
- Webster, M.-T., Pearce, B. R., Bowen, D. M., & Francis, P. T.
- Affiliations
- UCL Queen Square Institute of Neurology (GB)
- Venue
- Journal of Neural Transmission
- Published
- 1998-11-04
- Volume
- 105
- Issue
- 8-9
- Pages
- 839-853
- ISSN
- 0300-9564 (ISSN-L)
- 1435-1463
- OpenAlex
- W2147691616
- Cited by
- 62
- References
- 49
- Citations by year
- 2023: 2 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 3 · 2018: 7 · 2017: 4 · 2016: 4 · 2015: 2 · 2013: 1 · 2012: 3
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Neural Transmission (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- amyloid precursor protein, APP processing, Alzheimer's disease, energy metabolism, oxidative stress, PC12 cells, chloroquine, lysosomotropic agents, protein kinase C, APP secretion, amyloid-beta, metabolic stress, cholinomimetic drugs
- MeSH terms
- Animals, Antimetabolites, Bradykinin, Chloroquine, Deoxyglucose, Energy Metabolism, Immunologic Techniques, Nucleotides, Oligomycins, Protein Processing, Post-Translational, Reference Values, Amyloid beta-Protein Precursor, PC12 Cells, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
