Alzheimer’s Disease (AD) has been a topic of extensive research over the past three decades. The main focus of many studies has been the neurotoxicity associated with the accumulation of insoluble proteinaceous complexes in the brain. Closer examination has revealed these complexes to be plaques formed due to aggregation of small fragments of beta-amyloid peptides, which are proteolytic derivatives of a precursor protein APP (as a result of sequential action of two enzymes).
It has been known that beta-amyloid hyperactivated neurons led to neurotoxicity. However, a recent study published in Nature has shown that this was only one side of the story as far as pathogenesis of AD was concerned, shedding light on a new protein fragment characterized and called amyloid-η (eta-amyloid).
The research was conducted by an international team of researchers led by Christian Haass (Professor of Metabolic Biochemistry at LMU and Speaker for the German Center for Neurodegenerative Diseases in Munich) and Dr. Michael Willem (LMU), in collaboration with neurobiologist Dr. Hélène Marie based at the IPMC-CNRS in Valbonne (France) and with the local colleagues from the Technical University of Munich (TUM) in the Synergy Excellence Cluster (Professor Arthur Konnerth and Dr. Marc Aurel Busche).
Analysis of the functions of this newly characterized protein showed it acted as an antagonist when it came to beta-amyloid and its hyperactivity. In Dr. Haass’s words, “The processing pathway that produces it (eta-amyloid) has been overlooked for 30 years. This is because investigators including myself have focused their attention on elucidating the origins of the beta-amyloid and on attempts to cure Alzheimer’s by inhibiting production of this peptide. So here we have two small peptides snipped from the same precursor protein, which have opposite effects on neuronal activity, and whose actions must normally be carefully balanced.”
The findings of this study have had strong implications on all ongoing and upcoming clinical trials scheduled, all of which revolve around beta-amyloid. One such trial, designed to ascertain if the pharmacological inhibition of beta-secretase (the proteolytic enzyme that initiates the release of the toxic beta-amyloid from APP) can reduce memory loss in patients with Alzheimer’s, saw Dr. Haass and his colleagues conclude that blocking of beta-secretase did reduce the amount of beta-amyoid produced. However, it was also accompanied by a substantial increase in the amount of eta-amyloid secreted. Dr. Haass suggested this could result in unwanted and compromised brain function.
Based on these data, the authors advise that researchers should be on the lookout for any adverse side-effects related to the secretion of both these proteins during clinical trials.
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