Aftins Increase Amyloid-β42, Lower Amyloid-β38, and Do Not Alter Amyloid-β40 Extracellular Production in vitro: Toward a Chemical Model of Alzheimer's Disease?

Abstract

Increased production of amyloid-β (Aβ)42 peptide, derived from the amyloid-β protein precursor, and its subsequent aggregation into oligomers and plaques constitutes a hallmark of Alzheimer’s disease (AD). We here report on a family of low molecular weight molecules, the Aftins (Amyloid-β Forty-Two Inducers), which, in cultured cells, dramatically affect the production of extracellular/secreted amyloid peptides. Aftins trigger β-secretase inhibitor and γ-secretase inhibitors (GSIs) sensitive, robust upregulation of Aβ42, and parallel down-regulation of Aβ38, while Aβ40 levels remain stable. In contrast, intracellular levels of these amyloids appear to remain stable. In terms of their effects on Aβ38/Aβ40/Aβ42 relative abundance, Aftins act opposite to γ-secretase modulators (GSMs). Aβ42 upregulation induced by Aftin-5 is unlikely to originate from reduced proteolytic degradation or diminished autophagy. Aftin-5 has little effects on mitochondrial functional parameters (swelling, transmembrane potential loss, cytochrome c release, oxygen consumption) but reversibly alters the ultrastructure of mitochondria. Aftins thus alter the Aβ levels in a fashion similar to that described in the brain of AD patients. Aftins therefore constitute new pharmacological tools to investigate this essential aspect of AD, in cell cultures, allowing (1) the detection of inhibitors of Aftin induced action (potential ‘anti-AD compounds’, including GSIs and GSMs) but also (2) the identification, in the human chemical exposome, of compounds that, like Aftins, might trigger sustained Aβ42 production and Aβ38 down-regulation (potential ‘pro-AD compounds’).

Decrease in p3‐Alcβ37 and p3‐Alcβ40, products of Alcadein β generated by γ‐secretase cleavages, in aged monkeys and patients with Alzheimer's disease

“…We examined whether impaired or attenuated activity of γ‐secretase may be influencing p3‐Alcβ levels by using the γ‐secretase modulator Aftin‐5, which increases Aβ42 generation and to lower generation of Aβ38 [39]. Other studies have shown an identical trend in p3‐Alcα generation: it increases p3‐Alcα38 generation while decreasing that of p3‐Alcα35 [24].…”

Decrease in catalytic capacity of γ-secretase can facilitate pathogenesis in sporadic and Familial Alzheimer's disease

“…Decrease in γ-secretase activity can be a result of aging induced decrease in γ-secretase expression (Kern et al, 2006;Theuns et al, 2003). Different drug-candidates (Svedruzic et al, 2013;Mitani et al, 2012), and possibly environmental toxins (Hochard et al, 2013), can also decrease maximal activity of γ-secretase. Different pathogenic processes can be also simulated experimentally by decreasing expression of γ-secretase, or by increasing expression of APP substrate (German and Eisch, 2004;Marlow et al, 2003;Refolo et al, 1999).…”

High‐Throughput Screening of Marine Resources

“…Colorimetric (Lavery, Brown, and Pope, 2001), such as enzyme-linked immunosorbent assay (ELISA; Hochard et al, 2013). Fluorescent, such as fluorescence resonance energy transfer, (FRET; Mere et al, 1999;Zhu, Fu, and Luo, 2012), dissociation-enhanced lanthanide fluorescent immunoassay (DEL-FIA; Newbatt et al, 2013), fluorescence polarization (Owicki, 2000), time resolved-FRET (TR-FRET), homogeneous time-resolved fluorescence (HTRF; Degorce et al, 2009;von Ahsen et al, 2006), fluorogenic substrates (Mitnaul et al, 2007), calcium flux (Luo et al, 2011), and membrane translocation (Vijayakumar, Ajay, and Bhat, 2010).…”