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?

Article type: Research Article

Authors: Hochard, Arnaud^{a; b} | Oumata, Nassima^a | Bettayeb, Karima^c | Gloulou, Olfa^d | Fant, Xavier^b | Durieu, Emilie^{a; b} | Buron, Nelly^e | Porceddu, Mathieu^e | Borgne-Sanchez, Annie^e | Galons, Hervé^{a; d} | Flajolet, Marc^c | Meijer, Laurent^{a; *}

Affiliations: [a] ManRos Therapeutics, Centre de Perharidy, Roscoff, Bretagne, France | [b] CNRS, USR3151, Station Biologique, Roscoff, Bretagne, France | [c] Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA | [d] Laboratoire de Chimie Organique 2, CNRS, UMR 8601, Université Paris-Descartes, Paris, France | [e] Mitologics SAS, Hôpital Robert Debré, 48, Boulevard Sérurier, Paris, France

Correspondence: [*] Correspondence to: Laurent Meijer, ManRos Therapeutics, Centre de Perharidy, 29680 Roscoff, Bretagne, France. Tel.: +33 6 08 60 58 34; E-mail: meijer@manros-therapeutics.com.

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’).

Keywords: Aftins, Alzheimer's disease, amyloid-β, Aβ₃₈, Aβ₄₀, Aβ₄₂, γ-secretase, γ-secretase modulators, mitochondria

DOI: 10.3233/JAD-121777

Journal: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 107-120, 2013