Final Report Summary - AMYLOID (Identification and modulation of pathogenic Amyloid beta-peptide species)
Alzheimer's disease (AD) is the most abundant form of dementia worldwide. Due to our rapidly ageing society we have to expect a sharp increase of this devastating disease from currently about 50 million patients to more than 131 million patients in 2050. No cure is currently available. In order to provide treatment we need to understand the basic mechanisms, which lead to the disease and its progression, we must identify druggable therapeutic targets and we urgently need biomarkers to diagnose patients of risk as early as possible.
We identified a novel peptide that plays a central role in AD: The previously overlooked amyloid-eta (Aeta) interferes with neuronal function and may antagonize amyloid beta-peptide (Abeta) – a finding that has important implications for ongoing clinical trials.
AD is characterized by the accumulation of neurotoxic protein aggregates in various regions in the brain. Chemical analysis of these insoluble deposits revealed that they are composed of a family of short protein fragments, referred to Abeta, which are derived from a precursor protein called APP by the sequential action of two scissor-like enzymes. We have now made a discovery, which extends this picture of the pathogenesis of AD, by identifying a second and even more abundant processing pathway of APP. This involves a novel enzyme called eta-secretase. This processing pathway has been overlooked for 30 years. Moreover, 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) (Professor Arthur Konnerth and Dr. Marc Aurel Busche), we have also studied the effects of Aeta on nerve-cell function in the brain. Whereas Abeta is rendering nerve cells hyperactive, it turned out that Aeta antagonizes this effect. Apparently the two small peptides snipped from the same precursor protein have opposite effects on neuronal activity, and their action appears to be normally carefully balanced.
These findings have immediate implications for ongoing clinical trials in humans, where the proteolytic enzyme (beta-secretase) that initiates the release of the toxic beta-amyloid from APP is blocked. Although we fully confirmed that blocking the action of beta-secretase does reduce levels of Abeta this is accompanied by a massive increase in the amount of Aeta, which in turn reduces neuronal activity. This therefore suggests that clinicians need to be on the lookout for any signs of unanticipated side effects in the current clinical trials. Moreover, we found Aeta in the cerebrospinal fluid of humans and are now developing sensitive assays to monitor accumulation of this peptide in clinical trials. Furthermore, we have first evidence for a receptor, which mediates the neurotoxic activity of Aeta, and which may be pharmacologically blocked during beta-secretase treatment to prevent unwanted site effects.
We identified a novel peptide that plays a central role in AD: The previously overlooked amyloid-eta (Aeta) interferes with neuronal function and may antagonize amyloid beta-peptide (Abeta) – a finding that has important implications for ongoing clinical trials.
AD is characterized by the accumulation of neurotoxic protein aggregates in various regions in the brain. Chemical analysis of these insoluble deposits revealed that they are composed of a family of short protein fragments, referred to Abeta, which are derived from a precursor protein called APP by the sequential action of two scissor-like enzymes. We have now made a discovery, which extends this picture of the pathogenesis of AD, by identifying a second and even more abundant processing pathway of APP. This involves a novel enzyme called eta-secretase. This processing pathway has been overlooked for 30 years. Moreover, 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) (Professor Arthur Konnerth and Dr. Marc Aurel Busche), we have also studied the effects of Aeta on nerve-cell function in the brain. Whereas Abeta is rendering nerve cells hyperactive, it turned out that Aeta antagonizes this effect. Apparently the two small peptides snipped from the same precursor protein have opposite effects on neuronal activity, and their action appears to be normally carefully balanced.
These findings have immediate implications for ongoing clinical trials in humans, where the proteolytic enzyme (beta-secretase) that initiates the release of the toxic beta-amyloid from APP is blocked. Although we fully confirmed that blocking the action of beta-secretase does reduce levels of Abeta this is accompanied by a massive increase in the amount of Aeta, which in turn reduces neuronal activity. This therefore suggests that clinicians need to be on the lookout for any signs of unanticipated side effects in the current clinical trials. Moreover, we found Aeta in the cerebrospinal fluid of humans and are now developing sensitive assays to monitor accumulation of this peptide in clinical trials. Furthermore, we have first evidence for a receptor, which mediates the neurotoxic activity of Aeta, and which may be pharmacologically blocked during beta-secretase treatment to prevent unwanted site effects.