Abstract
The amyloid cascade hypothesis proposes that excessive accumulation of amyloid beta-peptides is the initiating event in Alzheimer's disease. These neurotoxic peptides are generated from the amyloid precursor protein via sequential cleavage by β- and γ-secretases in the 'amyloidogenic' proteolytic pathway. Alternatively, the amyloid precursor protein can be processed via the 'non-amyloidogenic' pathway which, through the action of the α-secretase a disintegrin and metalloproteinase (ADAM) 10, both precludes amyloid beta-peptide formation and has the additional benefit of generating a neuroprotective soluble amyloid precursor protein fragment, sAPPα. In the current study, we investigated whether the orphan drug, dichloroacetate, could alter amyloid precursor protein proteolysis. In SH-SY5Y neuroblastoma cells, dichloroacetate enhanced sAPPα generation whilst inhibiting β-secretase processing of endogenous amyloid precursor protein and the subsequent generation of amyloid beta-peptides. Over-expression of the amyloid precursor protein partly ablated the effect of dichloroacetate on amyloidogenic and non-amyloidogenic processing whilst over-expression of the β-secretase only ablated the effect on amyloidogenic processing. Similar enhancement of ADAM-mediated amyloid precursor protein processing by dichloroacetate was observed in unrelated cell lines and the effect was not exclusive to the amyloid precursor protein as an ADAM substrate, as indicated by dichloroacetate-enhanced proteolysis of the Notch ligand, Jagged1. Despite altering proteolysis of the amyloid precursor protein, dichloroacetate did not significantly affect the expression/activity of α-, β- or γ-secretases. In conclusion, dichloroacetate can inhibit amyloidogenic and promote non-amyloidogenic proteolysis of the amyloid precursor protein. Given the small size and blood-brain-barrier permeability of the drug, further research into its mechanism of action with respect to APP proteolysis may lead to the development of therapies for slowing the progression of Alzheimer's disease.
Highlights
The amyloid cascade hypothesis [1] states that the deposition of amyloid beta (Aβ)-peptides in the brain is the central event in the pathogenesis of the neurodegenerative condition, Alzheimer’s disease (AD)
We investigated whether the orphan drug, dichloroacetate, could alter amyloid precursor protein proteolysis
When cell lysates prepared from cultures grown in the presence of DCA were subjected to immunoblotting using anti-amyloid precursor protein (APP) C-terminal antibody, no significant changes were observed in levels of full-length APP (FL-APP) (Fig 1B)
Summary
The amyloid cascade hypothesis [1] states that the deposition of amyloid beta (Aβ)-peptides in the brain is the central event in the pathogenesis of the neurodegenerative condition, Alzheimer’s disease (AD) These neurotoxic peptides are generated from the larger amyloid precursor protein (APP) via the ’amyloidogenic’ pathway in which the protein is cleaved initially by β-secretase (β-site APP cleaving enzyme 1; BACE1) to liberate an N-terminal ectodomain termed sAPPβ and a residual beta C-terminal fragment (βCTF) [2]. The beneficial effects of the drug in these conditions stem from its ability to activate the pyruvate dehydrogenase complex (PDC) which catalyzes the irreversible oxidative phosphorylation of pyruvate to acetyl-Coenzyme A (acetyl-CoA) thereby reducing the amount of pyruvate available for conversion to lactate [10]. The activation of the PDC by DCA is thought to reinstate the latter as the main energy generating pathway in cancer cells thereby promoting mitochondrial-mediated apoptosis
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