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Updated: Sep 23, 2025
Imaging the Intracellular Trafficking of APP with Photoactivatable GFP
Published on: October 17, 2015
The amyloid precursor protein: a converging point in Alzheimer's disease
Alexandré Delport1, Raymond Hewer2
1Discipline of Biochemistry, School of Life Sciences, University of KwaZulu-Natal, Pietermaritzburg, 3201, South Africa. delporta1@ukzn.ac.za.
Abstract:
The decades of evidence that showcase the role of amyloid precursor protein (APP), and its fragment amyloidβ (Aβ), in Alzheimer's disease (AD) pathogenesis are irrefutable. However, the absolute focus on the single APP metabolite Aβ as the cause for AD has resulted in APP and its other fragments that possess toxic propensity, to be overlooked as targets for treatment. The complexity of its processing and its association with systematic metabolism suggests that, if misregulated, APP has the potential to provoke an array of metabolic dysfunctions. This review discusses APP and several of its cleaved products with a particular focus on their toxicity and ability to disrupt healthy cellular function, in relation to AD development. We subsequently argue that the reduction of APP, which would result in a concurrent decrease in Aβ as well as all other toxic APP metabolites, would alleviate the toxic environment associated with AD and slow disease progression. A discussion of those drug-like compounds already identified to possess this capacity is also included.
Insights
Alzheimer's disease (AD) research has focused on amyloid-beta (Aβ), overlooking other toxic amyloid precursor protein (APP) fragments. Reducing APP may slow AD progression by decreasing all toxic metabolites.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Decades of research link amyloid precursor protein (APP) and its fragment amyloid-beta (Aβ) to Alzheimer's disease (AD) pathogenesis.
- The singular focus on Aβ has led to the neglect of other toxic APP fragments as potential therapeutic targets.
- APP's complex processing and metabolic associations suggest its dysregulation can cause metabolic dysfunction.
Purpose of the Study:
- To review the toxicity of APP and its various cleaved products in relation to AD development.
- To highlight the potential of targeting APP itself, rather than solely Aβ, for AD treatment.
- To discuss compounds that can reduce APP levels.
Main Methods:
- Literature review of studies on APP processing, toxicity, and AD pathogenesis.
- Analysis of the role of various APP metabolites in cellular dysfunction.
- Identification and discussion of existing drug-like compounds with APP-reducing capabilities.
Main Results:
- APP and its fragments, beyond Aβ, exhibit toxicity and disrupt cellular function, contributing to AD.
- APP dysregulation is linked to broader metabolic dysfunctions.
- Several compounds have been identified that can reduce APP levels.
Conclusions:
- Reducing overall APP levels could decrease all toxic metabolites, including Aβ, thereby alleviating the toxic environment in AD.
- Targeting APP offers a promising strategy to slow Alzheimer's disease progression.
- Further investigation into APP-reducing compounds is warranted for AD therapeutic development.
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