Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage
William J Netzer1, Karima Bettayeb2, Subhash C Sinha2
1Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065 billnetzer@gmail.com greengard@rockefeller.edu.
Summary
The anticancer drug Gleevec reduces amyloid-β (Aβ) peptides, a hallmark of Alzheimer's disease (AD), by making amyloid precursor protein (APP) less vulnerable to BACE cleavage. This novel mechanism offers a potential therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Alzheimer's disease (AD) is driven by neurotoxic amyloid-β (Aβ) peptides.
- Aβ peptides are generated by sequential cleavage of amyloid precursor protein (APP) by β-secretase (BACE) and γ-secretase.
- Previous research indicated Gleevec indirectly inhibits γ-secretase, reducing Aβ levels.
Purpose of the Study:
- To investigate the additional mechanisms by which Gleevec lowers Aβ levels.
- To explore Gleevec's effect on APP processing by BACE.
- To evaluate the therapeutic potential of compounds modulating BACE processing for AD prevention.
Main Methods:
- Investigated Gleevec's effect on APP susceptibility to BACE cleavage.
- Analyzed APP C-terminal fragments induced by Gleevec.
- Tested a related compound (DV2-103) lacking tyrosine kinase inhibition in vitro and in vivo.
- Assessed compound accumulation in the rodent brain and Aβ lowering effects.
Main Results:
- Gleevec reduces APP susceptibility to BACE cleavage without inhibiting BACE activity or other substrate processing.
- This effect mimics the protective APP A673T mutation.
- Gleevec and DV2-103 induce specific APP C-terminal fragments, dependent on intracellular acidic pH.
- DV2-103 effectively lowers brain Aβ levels in rodents.
Conclusions:
- Gleevec employs a novel mechanism to lower Aβ by modulating APP processing by BACE.
- Compounds that indirectly modulate BACE processing of APP, spare other BACE substrates, and reach brain therapeutic concentrations may offer safer and effective AD treatments.
- This approach could prevent or delay Alzheimer's disease onset.
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