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-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').
ManRos Therapeutics, Centre de Perharidy, Roscoff, Bretagne, France.
Arnaud
A
Hochard
Nassima
N
Oumata
Karima
K
Bettayeb
Olfa
O
Gloulou
Xavier
X
Fant
Emilie
E
Durieu
Nelly
N
Buron
Mathieu
M
Porceddu
Annie
A
Borgne-Sanchez
Hervé
H
Galons
Marc
M
Flajolet
Laurent
L
Meijer
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008956:Models, Chemical; D010446:Peptide Fragments / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C579636:aftin-4; C078639:amyloid beta-protein (1-38); C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D000225:Adenine