S2‐03–04: Role of aminopeptidase NPPS in tauopathy

not available. S2-03-05 THE ROLE OF ACTIN AND OXIDATIVE STRESS IN TAU-ASSOCIATED NEURODEGENERATION Mel Feany, Harvard Medical School, Boston, MA, USA. Contact e-mail: mel_feany@hms.harvard.edu Background: Genetic models of Alzheimer’s disease in have been described in Drosophila. These models recapitulate key features of the human disorder and allow powerful genetic approaches to investigating pathogenesis. Methods: Transgenic Drosophila expressing human Abeta and tau in postmitotic neurons of the brain were created. Genetic, biochemical, and molecular techniques were used to investigate pathways mediating neurotoxicity of tau and Abeta. Results: Initially through forward genetic screens, a particular strength of the Drosophila system, a number of genetic pathways have been implicated in tau and Abeta neurotoxicity. Subsequent work has validated and investigated in detail a number of specific pathways including abnormal phosphorylation of tau, direct stabilization of filamentous actin by tau and subsequent production and toxicity of free radical species. Neuronal cell death is mediated by abnormal cell cycle activation, which induces apoptosis. Conclusions: Genetic analysis in simple model organisms like Drosophila offers a powerful method for exploring the molecular mechanisms underlying neurotoxcity in Alzheimer’s disease. S2-03-06 THE ROLE OF TAU IN AXONAL TRANSPORT AND NEURODEGENERATION Eva-Maria Mandelkow, Max-Planck Institute, Hamburg, Germany. Contact e-mail: mandelkow@mpasmb.desy.de Background: Abnormal changes in the properties of Tau protein are closely correlated with the progression of Alzheimer disease. They include aggregation into neurofibrillary tangles, hyperphosphorylation, missorting from the axons into the somatodendritic compartments of neurons. It is currently not well understood what causes the abnormal changes, and how they are related to the toxicity of Abeta, the decay of synapses, and the death of neurons. Methods: We have used different modes of live cell microscopy of primary neurons, adenoviral transfection of neurons with different variants of tau, and inducible transgenic mouse models of tauopathy. Results: The study mainly focussed on three facets of Tau: (1) By obstructing the surface of microtubules, Tau is capable, in principle, of slowing down axonal transport by inhibiting the attachment of motor proteins. This is particularly visible in the form of reduced mitochondrial movement, which in turn causes an energy crisis in the neuron by reducing the ATP level. As a result, synapses disintegrate, and synaptic markers disappear. (2) Although Tau is mostly a “microtubule-associated protein” (MAP), its residence time on microtubules is only a few seconds, and thus Tau is able to move through cytosolic space by diffusion with surprising speed. This may be one of the factors that enables Tau to enter the somatodendritic compartment, once the normal sorting mechanisms break down during Alzheimer disease. (3) There is a debate on whether the aggregation of Tau as such is toxic to neurons, or whether tau-induced toxicity depends on other factors. Using inducible cell and transgenic mouse models we find that the toxicity of Tau to neurons is tightly correlated with its ability to form beta-structure and to aggregate. Thus mutants of Tau that have a high beta-propensity show rapid aggregation and high toxicity, whereas mutants that are unable to aggregate are not toxic. Conclusions: The findings argue that the toxicity of Tau to neurons requires a particular pathological conformation which promotes beta-structure and tau-tau interactions. Using small molecule inhibitors it may be possible to prevent the pathological conformation and thus to keep Tau functional in the neuron without aggregation. MONDAY, JULY 28, 2008 SYMPOSIA S2-04 THERAPEUTICS: TOWARD DISEASE MODIFICATION S2-04-01 RECOMMENDATIONS AND OUTCOMES OF DISEASE-MODIFYING DRUGS Bruno Vellas, Purpan-Casselardit Hospital, Toulouse, France. Contact e-mail: vellas.b@chu-toulouse.fr Background: After symptomatic treatments, the new target for therapeutic approaches in the field of Alzheimer’s disease (AD) is the development of Disease Modifying Agents. The concept of disease-modification in AD is subject to debate and these trials raise many questions. Which population(s) should be studied? For how long? With which principal and secondary criteria? Are surrogate markers available? Complex diseases like Alzheimer’s Disease have many different, although interdependent, outcomes. Methods: Two International task Force (Lancet neurology 2007). Results: We present the point of vue of 2 European Task Force on disease modifying trials methodology and on endpoints to be used in clinical trials in Alzheimer’s disease, agreed under the auspices of the European Alzheimer Disease Consortium (EADC). We present here: the concept of disease modification; the study designs to be used; the role for biomarkers; and risk benefit and pharmaco-economic issues. Moreover suitable endpoints are suggested for the following types of trials: primary and secondary preventive trials, very early, mild, moderate, severe, and disease modifying AD trials. Conclusions: A clear and consensual definition of endpoints is a key element for the success of further clinical trials in the field and will allow comparison of data across studies. S2-04-02 DISEASE MODIFICATION: WILL WE KNOW IT WHEN WE SEE IT? Eric Siemers, Eli Lilly and Company, Indianapolis, IN, USA. Contact e-mail: esiemers@lilly.com Background: “Disease modification” is a frequently used term that has not yet been clearly defined with regard to Alzheimer’s disease (AD). Various primary and secondary outcome measures that might be used in clinical trials were evaluated with regard to their utility in understanding the effects of investigational treatments on the underlying pathophysiology and rate of clinical progression of AD. Methods: Outcomes using either clinical or biomarker measures to assess effects on underlying disease pathophysiology were evaluated. Clinical strategies include randomized start and randomized withdrawal designs. Biomarkers that might provide evidence of disease modification include volumetric magnetic resonance imaging (vMRI), 18F-fluoro-deoxy-glucose positron emission tomography (FDGPET), amyloid imaging, and biochemical measures including A 42 and tau concentrations in cerebrospinal fluid (CSF). Results: Each of the above measures is associated with certain advantages and certain limitations. While a randomized start design uses a clinical measure for assessment, uncertainties regarding statistical analyses and differential discontinuations among subjects prior to the end of the study may be confounding. For each of the various imaging and biochemical biomarkers, extant data suggest that they may not meet requirements for a surrogate marker of disease severity; nevertheless, each of these may provide important information regarding the effects of investigational drugs on brain structure and function. Conclusions: No single measure of “disease modification” is likely to provide compelling evidence that an investigational drug has caused an enduring change in the rate of clinical progression of AD. By understanding the effects of an investigational treatment on brain structure and function using biomarkers, and by examining the associated effects on T127 Symposia S2-04: Therapeutics: Toward Disease Modification