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?

Increased production of amyloid-beta (A beta)(42) peptide, derived from the amyloid-beta 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-beta Forty-Two Inducers), which, in cultured cells, dramatically affect the production of extracellular/secreted amyloid peptides. Aftins trigger beta-secretase inhibitor and gamma-secretase inhibitors (GSIs) sensitive, robust upregulation of A beta(42), and parallel down-regulation of A beta(38), while A beta(40) levels remain stable. In contrast, intracellular levels of these amyloids appear to remain stable. In terms of their effects on A beta(38)/A beta(40)/A beta(42) relative abundance, Aftins act opposite to gamma-secretase modulators (GSMs). A beta(42) 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 A beta 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 A beta(42) production and A beta(38) down-regulation (potential 'pro-AD compounds').