Aftins Increase Amyloid-β 42,Lower Amyloid-β 38,and Do Not Alter Amyloid-β 40 Extracellular Production in vitro: Toward a Chemical Model of Alzheimer's Disease?

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’).