Dataset Information

Justicidin A Reduces ?-Amyloid via Inhibiting Endocytosis of ?-Amyloid Precursor Protein.

ABSTRACT: ?-amyloid precursor protein (APP) can be cleaved by ?-, and ?-secretase at plasma membrane producing soluble ectodomain fragment (sAPP?). Alternatively, following endocytosis, APP is cleaved by ?-, and ?-secretase at early endosomes generating ?-amyloid (A?), the main culprit in Alzheimer's disease (AD). Thus, APP endocytosis is critical for A? production. Recently, we reported that Monsonia angustifolia, the indigenous vegetables consumed in Tanzania, improved cognitive function and decreased A? production. In this study, we examined the underlying mechanism of justicidin A, the active compound of M. angustifolia, on A? production. We found that justicidin A reduced endocytosis of APP, increasing sAPP? level, while decreasing A? level in HeLa cells overexpressing human APP with the Swedish mutation. The effect of justicidin A on A? production was blocked by endocytosis inhibitors, indicating that the decreased APP endocytosis by justicidin A is the underlying mechanism. Thus, justicidin A, the active compound of M. angustifolia, may be a novel agent for AD treatment.

SUBMITTER: Chun YS

PROVIDER: S-EPMC6513189 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Justicidin A Reduces β-Amyloid via Inhibiting Endocytosis of β-Amyloid Precursor Protein.

Chun Yoon Sun YS Kwon Oh-Hoon OH Oh Hyun Geun HG Cho Yoon Young YY Yang Hyun Ok HO Chung Sungkwon S

Biomolecules & therapeutics 20190501 3

β-amyloid precursor protein (APP) can be cleaved by α-, and γ-secretase at plasma membrane producing soluble ectodomain fragment (sAPPα). Alternatively, following endocytosis, APP is cleaved by β-, and γ-secretase at early endosomes generating β-amyloid (Aβ), the main culprit in Alzheimer's disease (AD). Thus, APP endocytosis is critical for Aβ production. Recently, we reported that <i>Monsonia angustifolia</i>, the indigenous vegetables consumed in Tanzania, improved cognitive function and decr ...[more]

PMID: 30332887

Similar Datasets

Project description: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.

Dataset Information

Justicidin A Reduces ?-Amyloid via Inhibiting Endocytosis of ?-Amyloid Precursor Protein.

Publications

Justicidin A Reduces β-Amyloid via Inhibiting Endocytosis of β-Amyloid Precursor Protein.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets