Alzheimer 2013 Jun-1

Abstract

Aβ Forty-Two INducers (AFTINs), low MW compounds triggering robust production of Aβ42 and down-regulation of Aβ38 in cell cultures

Despite extensive investigation, the causes and mechanisms underlying the initiation and development of Alzheimer’s disease (AD) still remain poorly understood. There is only a relatively mild consensus on the respective roles and importance of the two best described events associated with AD: (i) release of amyloid β peptides (Aβ) by proteolytic processing of the amyloid precursor protein (APP) and their extracellular aggregation in oligomers and plaques, (ii) hyperphosphorylation of the microtubule-binding protein Tau by various kinases and subsequent intracellular aggregation as paired helical filaments.

Enhanced production of Aβ42 and/or increase in the Aβ42/Aβ40 ratio appears as a critical factor in the onset of AD. Aβ42 is more toxic than Aβ40 and its higher hydrophobicity favors its ability to oligomerize and aggregate to form plaques. Despite numerous studies, the nature of the signals that modify the Aβ42/Aβ40/Aβ38 peptides relative abundance leading to increased production of toxic Aβ42 peptide observed in AD brain remains unknown. We here report on the discovery and characterization of Aftins (Amyloid β Forty-Two Inducers). These tri-substituted purines induce robust production of Aβ42 in cultured cells, down-regulate Aβ38, but leave Aβ40 unaffected. These effects are sensitive to γ-secretase modulators and inhibitors. Affinity chromatography on immobilized Aftins reveal that Aftins interact with mitochondrial proteins (VDAC, mitofilins, prohibitin), presenilins and APP. Aftins thus constitute new pharmacological tools to investigate the molecular mechanism underlying the modified Aβ42/Aβ40 ratioassociated with AD. Aftins may also be a first step towards a chemically induced animal model of AD.

Our cellular system allows (i) the detection of inhibitors of Aftin induced action (potential ‘anti-AD compounds’) and (ii) the identification of other compounds which, like Aftins, might trigger robust Aβ42 production and Aβ38 down-regulation (potential ‘pro-AD compounds’). The biological activity of Aftins suggests the potential existence of other pro-AD compounds in the ‘Human Chemical Exposome’. We believe that our simple screening test, using Aftin-5 as a positive reference compound, should be included in safety screens designed to detect potentially hazardous molecules among the large number of compounds that are already on or being brought to the market. These molecules may constitute environmental factors contributing to the onset, development and acceleration of AD. Their detection and identification would constitute a first step in a preventive action to reduce or even eradicate late onset AD which accounts for more than 99% of all AD cases.

References:

(1) Bettayeb, K., Oumata, N., Zhang, Y., Luo, W., Bustos, V., Galons, H., Greengard, P., Meijer, L. and Flajolet, M., 2012. Small molecule inducers of Aβ-42 peptide production share a common mechanism of action. FASEB J. 26, 5115-5123.

(2) Hochard, A., Oumata, N., Bettayeb, K., Gloulou, O., Fant, X., Buron, N., Porceddu, M., Borgne, A., Galons, H., Flajolet, M. and Meijer, L., 2013. Aftins increase amyloid-β42, lower amyloid-β38 and do not alter amyloid-β40 in vitro production: towards a chemical model of Alzheimer’s disease? J. Alzheimer’s Disease 35, 107-120.

Contact: Laurent Meijer, meijer@manros-therapeutics.com

 

Laurent Meijer

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