ArticleProceedings of the National Academy of Sciences of the United States of America2017
Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 27 citations in OpenAlex.
- Comparative Evaluation of Imatinib and Nilotinib in a Streptozotocin-Induced Rat Model of Alzheimer's Disease : Neuroprotective, Anti-inflammatory, and Cognitive Outcomes.Journal of Korean Neurosurgical Society · 2026Article
- The Hippo signaling pathway as a therapeutic target in Alzheimer's disease.Molecular neurodegeneration · 2025Review
- Experimental and clinical tests of FDA-approved kinase inhibitors for the treatment of neurological disorders (update 2024).Exploration of drug science · 2025Article
- Stretching the structural envelope of imatinib to reduce β-amyloid production by modulating both β- and γ-secretase cleavages of APP.Frontiers in chemistry · 2024Article
- Abl depletion via autophagy mediates the beneficial effects of quercetin against Alzheimer pathology across species.Cell death discovery · 2023Article
- FDA-Approved Kinase Inhibitors in Preclinical and Clinical Trials for Neurological Disorders.Pharmaceuticals (Basel, Switzerland) · 2022Review
- The Protective A673T Mutation of Amyloid Precursor Protein (APP) in Alzheimer's Disease.Molecular neurobiology · 2021Review
- Therapeutic Targeting of Repurposed Anticancer Drugs in Alzheimer's Disease: Using the Multiomics Approach.ACS omega · 2021Article
- Brain Permeable Tafamidis Amide Analogs for Stabilizing TTR and Reducing APP Cleavage.ACS medicinal chemistry letters · 2020Article
- Article
- Is Alzheimer's Disease a Liver Disease of the Brain?Journal of Alzheimer's disease : JAD · 2020Review
- Characterization of Cerebrospinal Fluid BACE1 Species.Molecular neurobiology · 2019Article
- Development of Kinase Inactive PD173955 Analogues for Reducing Production of Aβ Peptides.ACS medicinal chemistry letters · 2019Article
- Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease.The EMBO journal · 2017Article
- Not just amyloid: physiological functions of the amyloid precursor protein family.Nature reviews. Neuroscience · 2017Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Neurotoxic amyloid-β peptides (Aβ) are major drivers of Alzheimer's disease (AD) and are formed by sequential cleavage of the amyloid precursor protein (APP) by β-secretase (BACE) and γ-secretase. Our previous study showed that the anticancer drug Gleevec lowers Aβ levels through indirect inhibition of γ-secretase activity. Here we report that Gleevec also achieves its Aβ-lowering effects through an additional cellular mechanism. It renders APP less susceptible to proteolysis by BACE without inhibiting BACE enzymatic activity or the processing of other BACE substrates. This effect closely mimics the phenotype of APP A673T, a recently discovered mutation that protects carriers against AD and age-related cognitive decline. In addition, Gleevec induces formation of a specific set of APP C-terminal fragments, also observed in cells expressing the APP protective mutation and in cells exposed to a conventional BACE inhibitor. These Gleevec phenotypes require an intracellular acidic pH and are independent of tyrosine kinase inhibition, given that a related compound lacking tyrosine kinase inhibitory activity, DV2-103, exerts similar effects on APP metabolism. In addition, DV2-103 accumulates at high concentrations in the rodent brain, where it rapidly lowers Aβ levels. This study suggests that long-term treatment with drugs that indirectly modulate BACE processing of APP but spare other BACE substrates and achieve therapeutic concentrations in the brain might be effective in preventing or delaying the onset of AD and could be safer than nonselective BACE inhibitor drugs.
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