F1‐01‐01: Davunetide (AL‐108): Targeting tangles

not available. F1-01-03 PBT2 FOR ALZHEIMER’S DISEASE: AN UPDATE ON CLINICAL DEVELOPMENT Craig W. Ritchie, Ashley Bush, Imperial College London, London, United Kingdom; Massachusetts General Hospital, Boston, MA, USA. Contact e-mail: c.ritchie@imperial.ac.uk PBT2 is the lead Metal Protein Attenuating Compound (MPAC) being developed to treat Alzheimer’s disease (AD). The technological platform is based upon normalizing metal e protein interactions in the diseased brain. PBT2 has completed a Phase IIa study in patients with mild AD which demonstrated a reduction in Ab42 levels in CSF together with improved Executive Function performance in select cognitive tests following 12 weeks of treatment. Concurrent to this development, there has been a gathering academic interest in using MPACs for a variety of neurodegenerative conditions. Recent pre-clinical work has expanded upon initial observations regarding the importance of metals in the genesis of Alzheimer’s pathology which has led to a greater understanding of the potential benefits of MPACs for this condition. In animal studies, the effect of PBT2 on both biomarkers and cognition is measurable acutely and significantly suggesting that there may be a direct effect of this drug on the synaptotoxicity of Ab oligomers in a rapid time frame. Results from further analysis of the PBT2 Phase IIa study data will be presented and discussed. F1-01-04 BETA-SECRETASE AS TARGET FOR AMYLOIDREDUCTION THERAPY Jordan J. N. Tang, Oklahoma Medical Research Foundation,Oklahoma City, OK, USA. Contact e-mail: Jordan-Tang@omrf.ouhsc.edu Background: b-Secretase (memapsin 2, BACE1) is the protease that initiates the cleavage of amyloid precursor protein leading to the production of amiloid-b (Ab). Since an excess level of Ab in the brain is the major factor of Alzheimer’s disease (AD), b-secretase is an attractive target for the development of inhibitor drugs to treat this disease. Such a therapy would be expected to modify the progression of the disease. b-Secretase is a membrane anchored aspartic protease. The catalytic mechanism and inhibition of this class of protease is well known and the gene deletion of b-secretase is well tolerated in mice. Therefore, the research on this protease and the development of its inhibitors has been actively pursued over the last ten years. Methods: A steady progress, utilizing structure-based design cycles, has brought about inhibitors that contain many targeted characteristics of a drug. Results: Recent b-secretase inhibitors are relatively small, having good selectivity against other human aspartic proteases, capable of penetrating cell membranes and the blood-brain barrier, capable of reducing significantly Ab level in the brain of experimental animal models and successfully rescued age-related cognitive decline in transgenic mice. An advance inhibitor, CMT-21166, has been tested in Phase I clinical trial. Conclusions: These progresses in the development of memapsin 2 inhibitors suggest an optimistic outlook on the future of this line of drug development. F1-01-05 CONTROLLING SELF-ASSEMBLY AS A NOVEL PARADIGM FOR THE TREATMENT OF AMYLOID DISEASE Ehud Gazit, Tel Aviv University, Tel Aviv, Israel. Contact e-mail: EhudGa@tauex.tau.ac.il Abstract not available.not available. SUNDAY, JULY 12, 2009 FEATURED RESEARCH SYMPOSIA F1-02 N-TERMINALLY MODIFIED ABETA EMERGING TARGET IN ALZHEIMER’S DISEASE THERAPY F1-02-01 REGULATION OF PYROGLUTAMYL AMYLOID BETA PEPTIDE FORMATION BY NEPRILYSIN Takaomi C. Saido, Proteolytic Neuroscience Laboratory, RIKEN Brain Science Institute, Wako-shi, Japan. Contact e-mail: saido@brain.riken.jp Background: Amyloid beta peptide (Abeta) starting with pyroglutamate (pE) at position 3 is a dominant species that accumulates in the brains of AD patients, whereas APP Tg mice mainly accumulate Abeta1-40/42. Pyroglutamyl Abeta is more hydrophobic and metabolically more stable than others, and thus may play a specific role in AD pathogenesis. We first aimed to quantify N-truncated Abeta species in familial and sporadic AD cases and then to examine the relationship between neprilysin activity and pyroglutamyl Abeta formation. Methods: We first quantified N-terminally truncated species in AD brains using a series of endospecific antibodies. We then examined the effect of neprilysin deficiency on the neuropathology of APP-transgenic mice using immunohistochemical and mass spectrometric methods. Results: Abeta3(pE)-42 was consistently the predominant Abeta species in all AD brains examined. In APP-Tg mice, neprilysin deficiency augmented pathological accumulation of pyroglutamyl Abeta in a distinct manner. We also observed upregulation of