Final Report Summary - APOPIS (Abnormal proteins in the pathogenesis of neurodegenerative disorders)
The neurodegenerative diseases under investigation by the project include dementing disorders like Alzheimer's and Huntington's disease, frontotemporal dementia (FTD), Lewy body dementia (LBD) and transmissible spongiform encephalopathies or prion diseases, as well as movement disorders like Parkinson's disease, and motor neuron diseases like amyotrophic lateral sclerosis (ALS). Neither early diagnostic tools nor effective treatments existed at the time for these disorders.
A hallmark common to all of them is the deposition of abnormally folded protein aggregates in different brain regions. Yet, the events that trigger protein aggregation and the role these protein deposits play in disease progression are poorly understood. A small fraction of disease cases are associated with genetic mutations and the identification of disease-related genes with their subsequent characterisation in cell culture and animal models has provided invaluable insights into the underlying pathological processes. However, the list of genes associated with neurodegenerative disorders is far from being complete and only little is known about the role of the encoded proteins, both in normal and pathologic conditions.
The consortium was established to provide a better understanding of the pathogenic mechanisms involved in neurodegeneration, to advance clinical detection and to develop strategies for the prevention and treatment of these disorders. It integrated 39 research groups from all over Europe to tackle the tasks in a multifaceted approach, combining different disciplines to provide a more comprehensive view of the problem of protein aggregation and how it triggers neurodegeneration.
Substantial progress in the understanding of the various neurodegenerative conditions was achieved in the course of the project. This was reflected by a number of high-impact publications, many of them resulting from collaborations between partners.
For all the neurodegenerative conditions, there is a frustrating lack of effective treatments. Available treatments can in the best of cases delay disease progression and temporarily ameliorate some of the symptoms. Abeta immunotherapy was shown to be beneficial in transgenic mouse models and members of this consortium were the first to show beneficial effects also in AD patients in a phase II clinical trial from ELAN/Wyeth-Ayerst. To avoid/reduce the immunisation-related meningoencephalitis observed in some of the patients (and which halted the clinical trial), partners invested in the development of passive vaccination strategies.
In one of the approaches, they isolated and immortalised memory B cells from vaccinated patients that showed strong antibody response and reduced cognitive decline in the phase II trial. One of the B cell clones produced an antibody, TAP-1, that specifically stained human amyloid-plaques on tissue sections of human AD brain. Partners further characterised this antibody in a number of assays and could show that it has a higher affinity for fibrillar than for monomeric forms of Abeta. Thus, the TAP-1 antibody might detect neo-epitopes generated by the pathologic aggregation of Abeta peptides. They then evaluated the therapeutic efficacy of this antibody in transgenic mouse models of AD. Preliminary analysis demonstrated that a small fraction of the antibody had crossed the blood- brain barrier, and that there were no significant haemorrhages. In a separate approach, they developed conformation-specific monoclonal antibodies that bind specifically to Abeta protofibrils and were effective in reducing protofibrils-induced toxicity in cultured cells.
They then tested these antibodies in the APPArcSwe mouse AD model. Preliminary data suggested markedly lower Abeta protofibril levels and modestly lower levels of total insoluble Abeta in the brains of treated mice. Altogether these data, although preliminary, supported passive Abeta vaccination as a promising treatment for AD patients.
The results of research conducted within the APOPIS project, many of them deriving from collaborations between various partners, were reported to the scientific community in about 200 mostly high-impact, peer-reviewed journals and at high-profile international conferences. At many occasions the public was informed about the increasing societal and economic burden of neurodegenerative diseases due to the growing human life expectancy all over the world. Public awareness was raised for the fact that the consequences of this development can only be averted by successful research efforts resulting in the development of reliable preventive and therapeutic interventions.
Several contractors followed the advice of the Commission to withhold information on their results due to intellectual property rights (IPR) reasons. Altogether, the APOPIS project contributed to achieving the Lisbon Agenda's goals of growth, competitiveness and employment, not only by the scientific progress reached, but also by successfully combining the scattered European resources in the area of research, which will certainly come to fruition only in the near future.
A hallmark common to all of them is the deposition of abnormally folded protein aggregates in different brain regions. Yet, the events that trigger protein aggregation and the role these protein deposits play in disease progression are poorly understood. A small fraction of disease cases are associated with genetic mutations and the identification of disease-related genes with their subsequent characterisation in cell culture and animal models has provided invaluable insights into the underlying pathological processes. However, the list of genes associated with neurodegenerative disorders is far from being complete and only little is known about the role of the encoded proteins, both in normal and pathologic conditions.
The consortium was established to provide a better understanding of the pathogenic mechanisms involved in neurodegeneration, to advance clinical detection and to develop strategies for the prevention and treatment of these disorders. It integrated 39 research groups from all over Europe to tackle the tasks in a multifaceted approach, combining different disciplines to provide a more comprehensive view of the problem of protein aggregation and how it triggers neurodegeneration.
Substantial progress in the understanding of the various neurodegenerative conditions was achieved in the course of the project. This was reflected by a number of high-impact publications, many of them resulting from collaborations between partners.
For all the neurodegenerative conditions, there is a frustrating lack of effective treatments. Available treatments can in the best of cases delay disease progression and temporarily ameliorate some of the symptoms. Abeta immunotherapy was shown to be beneficial in transgenic mouse models and members of this consortium were the first to show beneficial effects also in AD patients in a phase II clinical trial from ELAN/Wyeth-Ayerst. To avoid/reduce the immunisation-related meningoencephalitis observed in some of the patients (and which halted the clinical trial), partners invested in the development of passive vaccination strategies.
In one of the approaches, they isolated and immortalised memory B cells from vaccinated patients that showed strong antibody response and reduced cognitive decline in the phase II trial. One of the B cell clones produced an antibody, TAP-1, that specifically stained human amyloid-plaques on tissue sections of human AD brain. Partners further characterised this antibody in a number of assays and could show that it has a higher affinity for fibrillar than for monomeric forms of Abeta. Thus, the TAP-1 antibody might detect neo-epitopes generated by the pathologic aggregation of Abeta peptides. They then evaluated the therapeutic efficacy of this antibody in transgenic mouse models of AD. Preliminary analysis demonstrated that a small fraction of the antibody had crossed the blood- brain barrier, and that there were no significant haemorrhages. In a separate approach, they developed conformation-specific monoclonal antibodies that bind specifically to Abeta protofibrils and were effective in reducing protofibrils-induced toxicity in cultured cells.
They then tested these antibodies in the APPArcSwe mouse AD model. Preliminary data suggested markedly lower Abeta protofibril levels and modestly lower levels of total insoluble Abeta in the brains of treated mice. Altogether these data, although preliminary, supported passive Abeta vaccination as a promising treatment for AD patients.
The results of research conducted within the APOPIS project, many of them deriving from collaborations between various partners, were reported to the scientific community in about 200 mostly high-impact, peer-reviewed journals and at high-profile international conferences. At many occasions the public was informed about the increasing societal and economic burden of neurodegenerative diseases due to the growing human life expectancy all over the world. Public awareness was raised for the fact that the consequences of this development can only be averted by successful research efforts resulting in the development of reliable preventive and therapeutic interventions.
Several contractors followed the advice of the Commission to withhold information on their results due to intellectual property rights (IPR) reasons. Altogether, the APOPIS project contributed to achieving the Lisbon Agenda's goals of growth, competitiveness and employment, not only by the scientific progress reached, but also by successfully combining the scattered European resources in the area of research, which will certainly come to fruition only in the near future.
