Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

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.Alzheimer's disease | Gleevec | nonamyloidogenic | β-cleavage

Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP Processing

“…The levels of aCTFs and bCTFs did not differ between SORL1-KO and WT neurons under DMSO conditions, although we observed an increase in aCTFs in WT neurons with BACEi treatment (Figures 4A-4C). This suggests that a cleavage may be exacerbated under these conditions, as aand b-secretase have been shown to have competitive activity (Netzer et al, 2017;Skovronsky et al, 2000). We did not observe an increase in aCTFs in SORL1-KO neurons (Figures 4A-4C), which is consistent with the observation that loss of SORL1 retains APP in the early endosome, where it is unavailable for a cleavage.…”

Fyn Tyrosine Kinase Elicits Amyloid Precursor Protein Tyr682 Phosphorylation in Neurons from Alzheimer’s Disease Patients

“…In animal studies, TKI-induced inhibition of the TK Abl increases Aβ clearance, and attenuates behavioral deficits [67]. Imatinib, a small-molecule TKI, ameliorates neurodegenerative changes in animal models of AD through the transcriptional induction of genes that are involved in the clearance of Aβ fibrils, in the regulation of apoptosis, and in the decrease of pathological tau protein hyperphosphorylation [65,67,68]. Other TKIs, such as nilotinib and bosutinib, can efficiently cross the blood-brain barrier and have been proposed to be potential treatments for AD and Parkinson's disease [69,70].…”

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

“…Treatment with BI reduced the incorporation of cholesterol into cholesteryl esters ( Fig 3C) and reduced the number of LDs in PS-DKO cells, in AD patient fibroblasts ( Fig 3D), and in PS1-KI M146V mouse astrocytes and cortical neurons (Appendix Fig S3A). Similarly, treatment of PS-DKO cells with Gleevec, an anticancer drug that has been recently shown to reduce APP cleavage by BACE (Netzer et al, 2017), resulted in a significant reduction of LDs in PS-DKO cells (Appendix Fig S3B). Lipid droplets also accumulated in SH-SY5Y and HeLa cells treated with DAPT alone (i.e., increasing C99), which was reversed in cells treated with DAPT+BI (i.e., preventing C99 formation) (Appendix Fig S3C).…”