This is remarkable, since this new peptide, amyloid-η (amyloid-eta), is naturally produced in the brain and affects neuronal function: this discovery could have implications for ongoing clinical trials. This work is an international collaborative effort between German teams from DZNE, TU München, and LMU München1 and a French team from the Institut de pharmacologie moléculaire et cellulaire (CNRS/Université Nice Sophia Antipolis). It is published on August 31, 2015 in Nature.
Although it is produced in larger quantities than amyloid-β, amyloid-η had been entirely overlooked for thirty years. Neuroscientists focused on amyloid-β: how it is produced and accumulates, how toxic it is to neurons and how to inhibit it to treat Alzheimer’s disease. In this study, after having identified it both in model mice brains and in patients’ brains, the researchers showed that this novel peptide reduces the synapse strengthening that is necessary for forming memories, just like amyloid-β does2. Moreover, by contrast with amyloid-β, which makes neurons hyperactive, amyloid-η makes them harder to excite. In light of its neurotoxicity, this novel peptide is no doubt involved in the mechanism of Alzheimer’s disease, but other work will be necessary to determine how it affects cognitive deficits.
This discovery does have immediate consequences on ongoing clinical trials, most of which aim to reduce the amount of amyloid-β in the hope of stopping memory loss. For example, one of these clinical trials studies the inhibition of β-secretase, a key enzyme involved in amyloid-β formation. The researchers have now confirmed that inhibiting this enzyme reduces amyloid-β production but that this is accompanied by a massive increase in amyloid-η. It is therefore highly probable that this therapeutic strategy could harm the brain, due to excessive amyloid-η action on neurons. Investigators should therefore be on the lookout for possible unanticipated side effects in clinical trials.
1 DZNE: Deutsches Zentrum für Neurodegenerative Erkrankungen; TU München: Technische Universität München; LMU München: Ludwig-Maximilians-Universität München.
2 A type of plasticity called long-term potentiation (LTP).
η-Secretase processing of APP inhibits neuronal activity in the hippocampus, Michael Willem, Sabina Tahirovic, Marc Aurel Busche, Saak V. Ovsepian, Magda Chafai, Scherazad Kootar, Daniel Hornburg, Lewis D.B. Evans, Steven Moore, Anna Daria, Heike Hampel, Veronika Müller, Camilla Giudici, Brigitte Nuscher, Andrea Wenninger-Weinzierl, Elisabeth Kremmer, Michael T. Heneka, Dietmar R. Thal, Vilmantas Giedraitis, Lars Lannfelt, Ulrike Müller, Frederick J. Livesey, Felix Meissner, Jochen Herms, Arthur Konnerth, Hélène Marie & Christian Haass. Nature , August 31, 2015. DOI:10.1038/nature14864
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