Abstract
Amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer’s disease (AD), due to its neurotoxicity. Thus, blocking Aβ generation and aggregation in the brain has been realized as an efficient way for the prevention of AD. The natural product catalpol, isolated from Rehmannia glutinosa, has shown neuroprotective activities through inhibiting soluble Aβ production, degrading Aβ peptide, and attenuating Aβ toxicity and neuroinflammatory responses. In the present study, we aimed to evaluate whether catalpol reduce Aβ generation associated with regulating amyloid precursor protein (APP) proteolytic processing. By using Swedish mutant APP overexpressed N2a (SweAPP N2a) cells treated with catalpol, we found that catalpol was not able to reduce the expression levels of β-secretase (BACE-1) and γ-secretase (PS1, APH-1, PEN-2 and Nicastrin). By contrast, catalpol had a significant promotion effect on the expression of α-secretase (ADAM10) and its proteolytic products, sAPPα and C83, suggesting that catalpol reduced the production of Aβ might be involved in non-amyloidogenic APP pathway. In addition, we confirmed that the extracellular signal-related kinase/cAMP-response element binding protein (ERK/CREB) signaling pathways were responsible for the up-regulation of ADAM10 in catalpol-treated SweAPP N2a cells. The present data, for the first time, have demonstrated that the effect of catalpol on the inhibiting Aβ generation might be closely related to α-cleavage of APP processing.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder mainly occurred in the elderly
By using Swedish mutant amyloid precursor protein (APP) overexpressed N2a (SweAPP N2a) cells, we found that catalpol could promote the non-amyloidogenic APP processing through up-regulating ADAM10 expression
Through using this culture system, we first analyzed if catalpol treatment could inhibit APP expression and Aβ production
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder mainly occurred in the elderly. To block Aβ generation and aggregation has been realized as one of the most important strategies for preventing and treating AD. It is well-known that Aβ is generated from amyloid precursor protein (APP). The transmembrane APP protein is cleaved by β-secretase (BACE-1) and γ-secretase to generate the small peptide, Aβ (Cao et al, 2016). A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is a major α-secretase for APP cleavage, and plays an important role in inhibiting Aβ production (Postina et al, 2004; Kuhn et al, 2010; Yuan et al, 2017). BACE-1 and ADAM10 have been considered as the major drug targets for combating AD
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