Symposia S2-01: Progress in Genetic Research 3) Frank R, Hargreaves, Nat Rev Drug Discov. 2003,7; 2(7):566-80 4) Smith D, Proc Natl Acad Sci U S A. 2002,4,2; 99(7): 4135-4137 5) Ashburner J et al., Lancet Neurol. 2003, 2;2(2):79-88 PL-02-02 BETA-SECRETASE AS A THERAPEUTIC TARGET Martin O. Citron, Amgen, Thousand Oaks, CA, USA. Contact e-mail: mcitron@amgen.com Finding inhibitors of A␤42 generation is a major goal of Alzheimer’s disease drug development. Two target protease activities, ␤-and ␥-secretase, were operationally defined in the early 90s, but progress in this area was slow, because the actual enzymes were not understood at the molecular level. Some years ago we identified a novel membrane bound aspartic protease, BACE1, as ␤-secretase. This finding has been confirmed and BACE1 and its homolog BACE2 have been characterized in detail by many groups. Major progress has been made in two areas: First, the x-ray crystal structure, which is critical for rational inhibitor design, has been solved and shown to be similar to that of other pepsin family members. Second, knockout studies show that BACE1 is critical for A␤ generation, but the knockout mice show an otherwise normal phenotype, raising the possibility that therapeutic BACE1 inhibition could be accomplished without major mechanism based toxicity. However, target-mediated toxicity of ␤-secretase inhibition cannot be ruled out based on the currently available data alone. While various peptidic ␤-secretase inhibitors have been published, the key challenge now is the generation of more drug-like compounds that could be developed for therapeutic purposes. Other current areas of investigation, including identification of additional BACE1 substrates, the potential role of BACE1 overexpression in AD and the phenotype of BACE2 knockout mice will be discussed. PL-02-03 TAU AND TAUOPATHIES Jesus Avila, Universidad Autonoma de Madrid, Madrid, Spain. Contact e-mail: javila@cbm.uam.es Background: Tau, a microtubule associated protein, can aberrantly polymerize, in phosphorylated form, yielding the paired helical filaments found in the brain of Alzheimer’s disease patients. Objective(s): Our purpose is to know tau pathology related with its phosphorylation and its assembly. Methods: In vitro analysis and the use of mouse models. Conclusions: Tau assembly can be reproduced in vitro by mixing tau protein with polymerization inducers like heparin or Coenzyme Q0, being the assembly of phosphotau facilitated in the presence of Co.Q0. Polymerization of tau has been also mimified by using transgenic mouse models. In these models, human tau, bearing some of the mutations found in patients with FTDP-17, was expressed. Mutations on APP and/or PS-1 will facilitate tau phosphorylation by kinases like GSK3. Thus, a transgenic mouse model overexpressing GSK3 was also characterized. In some of these mouse models, a link between tau phosphorylation and tau assembly has been established. Finally, the possible toxic effect of phosphotau or tau aggregates will be discussed. MONDAY, JULY 17, 2006 SYMPOSIA S2-01 PROGRESS IN GENETIC RESEARCH S2-01-01 SYSTEMATIC META-ANALYSIS OF ALZHEIMER’S DISEASE GENETIC ASSOCIATION STUDIES - THE ALZGENE DATABASE S23 suggest that the common late-onset form of AD is caused by a variety of independent genetic (and non-genetic) risk factors. In the past decade, literally hundreds of reports have been published claiming or refuting genetic association with putative AD genes, and currently nearly 10 association studies are published each month. For the research community as well as the public this wealth of information has become increasingly difficult to follow, evaluate and—most importantly—to interpret. To better understand these findings, we have created a comprehensive and publicly available database (“AlzGene”; hosted by the Alzheimer Research Forum, available at www.alzgene.org) which systematically collects and summarizes all genetic association studies in the field of AD. In addition to displaying essential details for each study (e.g., sample sizes, onset age, genotype numbers), the database provides up-to-date summary effect size estimates and assessments of publication bias for each polymorphism across all studies. The results of these meta-analyses should help to better distinguish the relevant AD risk genes from false-positive reports as well as those with negligible effects. Currently, the AlzGene database includes nearly 1,000 individual studies of over 300 different candidate genes. At the meeting we will present a comprehensive summary of these metaanalyses with a particular focus on genes which significantly increase or decrease the risk for AD. S2-01-02 IDENTIFICATION OF NOVEL GENES AND MUTATIONS IN ALZHEIMER DISEASE Christine Van Broeckhoven, VIB8 - Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, University of Antwerp, Antwerpen, Belgium. Contact e-mail: christine.vanbroeckhoven@ua.ac.be Background: Alzheimer disease (AD) is genetically heterogeneous with both causal and susceptibility genes contributing to its genetic etiology. The current genes and mutations explain approximately 80%, indicating that several other genetic factors remain to be identified. Objectives: To identify novel genes and mutation mechanisms underlying the risk for both early- and late-onset AD. Methods: We systematically sample patients with AD using a standardized protocol for phenotyping including an extensive clinical examination, memory tests and brain imaging. Also biochemical data is collected of biomarkers analyzed in cerebrospinal fluid and serum, and in autopsied brain. In all patients we determine the APOE genotype. In patients with onset age ⬍70 years mutation analysis is performed of 5 dementia genes: APP, PSEN1, PSEN2, MAPT and PRNP. Of each index patient we sample the spouse and children, and in case of a positive family history all cooperative family members are sampled for genome-wide segregation and association studies using STR and/or SNP markers. Results: In a series of 180 early-onset AD patients we identified 1 APP mutation (Val717Ile, 0.5%), 3 APP promoter mutations that increase APP transcription (1.7%) but no APP genomic duplication mutations. Of some milder APP promoter mutations the frequency increased with onset age. We also identified 6 mutations in PSEN1 and PSEN2 (3.3%). In 1 AD patient, with an onset age of 69 years, we detected a PRNP octapeptide insertion and in MAPT we found the intron 10 (IVS10⫹29G⬎A) variant of which the pathogenic nature is still controversial. Conclusions: Together, our data suggest that the frequency of mutations in the five dementia genes is around 6%. Of interest is the observation of several mutations in patients with onset ⬎65 years and duration of disease in old age, suggesting that some mutations have a milder pathogenic effect. S2-01-03 SYSTEMATIC SCREENS IDENTIFY NOVEL GENES FOR LOAD SUSCEPTIBILITY ON CHROMOSOMES 9 AND 10 Lars Bertram1, Matthew B. McQueen2, Kristina Mullin1, Deborah Blacker1,2, Rudolph E. Tanzi1, 1Massachusetts General Hospital, Charlestown, MA, USA; 2Harvard School of Public Health, Boston, MA, USA. Contact e-mail: bertram@helix.mgh.harvard.edu Alison M. Goate, Washington University School of Medicine, St. Louis, MO, USA. Contact e-mail: goate@icarus.wustl.edu Alzheimer’s disease (AD) is a genetically complex and heterogeneous disorder showing an age-dependent dichotomy. Several lines of evidence Background: Late-onset AD (LOAD) probably results from the combined effects of variation in a number of genes as well as environmental factors.