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Small-molecule inducers of A?-42 peptide production share a common mechanism of action.

ABSTRACT: The pathways leading specifically to the toxic A?42 peptide production, a key event in Alzheimer's disease (AD), are unknown. While searching for pathways that mediate pathological increases of A?42, we identified Aftin-4, a new compound that selectively and potently increases A?42 compared to DMSO (N2a cells: 7-fold; primary neurons: 4-fold; brain lysates: 2-fold) with an EC(50) of 30 ?M. These results were confirmed by ELISA and IP-WB. Using affinity chromatography and mass spectrometry, we identified 3 proteins (VDAC1, prohibitin, and mitofilin) relevant to AD that interact with Aftin-4, but not with a structurally similar but inactive molecule. Electron microscopy studies demonstrated that Aftin-4 induces a reversible mitochondrial phenotype reminiscent of the one observed in AD brains. Sucrose gradient fractionation showed that Aftin-4 perturbs the subcellular localization of ?-secretase components and could, therefore, modify ?-secretase specificity by locally altering its membrane environment. Remarkably, Aftin-4 shares all these properties with two other "AD accelerator" compounds. In summary, treatment with three A?42 raising agents induced similar biochemical alterations that lead to comparable cellular phenotypes in vitro, suggesting a common mechanism of action involving three structural cellular targets.

SUBMITTER: Bettayeb K

PROVIDER: S-EPMC3509055 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Small-molecule inducers of Aβ-42 peptide production share a common mechanism of action.

Bettayeb Karima K Oumata Nassima N Zhang Yuanyuan Y Luo Wenjie W Bustos Victor V Galons Hervé H Greengard Paul P Meijer Laurent L Flajolet Marc M

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20120912 12

The pathways leading specifically to the toxic Aβ42 peptide production, a key event in Alzheimer's disease (AD), are unknown. While searching for pathways that mediate pathological increases of Aβ42, we identified Aftin-4, a new compound that selectively and potently increases Aβ42 compared to DMSO (N2a cells: 7-fold; primary neurons: 4-fold; brain lysates: 2-fold) with an EC(50) of 30 μM. These results were confirmed by ELISA and IP-WB. Using affinity chromatography and mass spectrometry, we id ...[more]

PMID: 22972917

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Project description:Human mini-brains (MB) are cerebral organoids that recapitulate in part the complexity of the human brain in a unique three-dimensional in vitro model, yielding discrete brain regions reminiscent of the cerebral cortex. Specific proteins linked to neurodegenerative disorders are physiologically expressed in MBs, such as APP-derived amyloids (A?), whose physiological and pathological roles and interactions with other proteins are not well established in humans. Here, we demonstrate that neuroectodermal organoids can be used to study the A? accumulation implicated in Alzheimer's disease (AD). To enhance the process of protein secretion and accumulation, we adopted a chemical strategy of induction to modulate post-translational pathways of APP using an Amyloid-? Forty-Two Inducer named Aftin-5. Secreted, soluble A? fragment concentrations were analyzed in MB-conditioned media. An increase in the A?42 fragment secretion was observed as was an increased A?42/A?40 ratio after drug treatment, which is consistent with the pathological-like phenotypes described in vivo in transgenic animal models and in vitro in induced pluripotent stem cell-derived neural cultures obtained from AD patients. Notably in this context we observe time-dependent A? accumulation, which differs from protein accumulation occurring after treatment. We show that mini-brains obtained from a non-AD control cell line are responsive to chemical compound induction, producing a shift of physiological A? concentrations, suggesting that this model can be used to identify environmental agents that may initiate the cascade of events ultimately leading to sporadic AD. Increases in both A? oligomers and their target, the cellular prion protein (PrPC), support the possibility of using MBs to further understand the pathophysiological role that underlies their interaction in a human model. Finally, the potential application of MBs for modeling age-associated phenotypes and the study of neurological disorders is confirmed.

Project description:BackgroundA key histopathological hallmark of Alzheimer's disease (AD) is the presence of neurofibrillary tangles of aggregated microtubule-associated protein tau in neurons. Anle138b is a small molecule which has previously shown efficacy in mice in reducing tau aggregates and rescuing AD disease phenotypes.MethodsIn this work, we employed bioinformatics analysis-including pathway enrichment and causal reasoning-of an in vitro tauopathy model. The model consisted of cultured rat cortical neurons either unseeded or seeded with tau aggregates derived from human AD patients, both of which were treated with Anle138b to generate hypotheses for its mode of action. In parallel, we used a collection of human target prediction models to predict direct targets of Anle138b based on its chemical structure.ResultsCombining the different approaches, we found evidence supporting the hypothesis that the action of Anle138b involves several processes which are key to AD progression, including cholesterol homeostasis and neuroinflammation. On the pathway level, we found significantly enriched pathways related to these two processes including those entitled "Superpathway of cholesterol biosynthesis" and "Granulocyte adhesion and diapedesis". With causal reasoning, we inferred differential activity of SREBF1/2 (involved in cholesterol regulation) and mediators of the inflammatory response such as NFKB1 and RELA. Notably, our findings were also observed in Anle138b-treated unseeded neurons, meaning that the inferred processes are independent of tau pathology and thus represent the direct action of the compound in the cellular system. Through structure-based ligand-target prediction, we predicted the intracellular cholesterol carrier NPC1 as well as NF-κB subunits as potential targets of Anle138b, with structurally similar compounds in the model training set known to target the same proteins.ConclusionsThis study has generated feasible hypotheses for the potential mechanism of action of Anle138b, which will enable the development of future molecular interventions aiming to reduce tau pathology in AD patients.

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Small-molecule inducers of A?-42 peptide production share a common mechanism of action.

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Small-molecule inducers of Aβ-42 peptide production share a common mechanism of action.

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