S4–03–03: Dual effect of tau hyperphosphorylation in cell apoptosis and cell degeneration

not available. S4-03-06 EXPLORING REVERSAL OF ALZHEIMER’S DISEASE LIKE PHENOTYPE IN A MOUSE MODEL WITH CONDITIONAL OVEREXPRESSION OF GSK-3 Jose J. Lucas, Tobias Engel, Jesus Avila, Felix Hernandez, CSIC/UAM CBM, Madrid, Spain. Contact e-mail: jjlucas@cbm.uam.es Glycogen synthase kinase-3 (GSK3) is a ubiquitously expressed serine/ threonine kinase that is particularly abundant in the CNS. Dysregulation of GSK-3 activity is believed to play a key role in the pathogenesis of CNS chronic disorders such as Alzheimer’s disease (AD), bipolar disorder and Huntington’s disease, and of metabolic disorders such as Type-II diabetes. Accordingly, GSK-3 inhibitors have been postulated as therapeutic tools for these diseases. Interestingly, pathophysiological and pharmacological regulation of GSK-3 is affected by an amplification mechanism that applies both to inhibition and activation. The possibility therefore exists that sustained inhibition or activation might persist upon cessation of the initial trigger. Regarding AD, GSK-3 has been shown to be upregulated in patients’ brain. Furthermore, GSK-3 phosphorylates tau in most serine and threonine residues hyperphosphorylated in paired helical filament (PHF)tau and GSK-3 activity contributes both to -amyloid production and to -amyloid-mediated neuronal death. In good agreement, mice with conditional overexpression of GSK-3 in forebrain neurons (Tet/GSK-3 mice) recapitulate aspects of AD neuropathology such as tau hyperphosphorylation, apoptotic neuronal death, and reactive astrocytosis as well as spatial learning deficit. Here we aim to exploit the conditional system used to generate Tet/GSK-3 mice to explore whether the biochemical, histopathological, and behavioral consequences of increased GSK-3 activity are susceptible to revert upon restoration of normal GSK-3 levels. WEDNESDAY, JULY 19, 2006 SYMPOSIA S4-04 DRUG DISCOVERY (CLINICAL TRIALS) S4-04-01 BEYOND ACETYLCHOLINESTERASE INHIBITORS: NOVEL APPROACHES FOR THE TREATMENT OF ALZHEIMER’S DISEASE Menelas N. Pangalos, Jack S. Jacobsen, Peter H. Reinhart, Wyeth Research, Monmouth Junction, NJ, USA. Contact e-mail: pangalm@wyeth.com Background: Alzheimer’s disease is a complex neurodegenerative disease affecting over 4 million people in the US at a cost of over $1 billion dollars per year. With the baby boomer generation living longer every year, predictions suggest that we could have over 20 million people suffering from Alzheimer’s disease by 2050. The socio-economic implications of this explosion of Alzheimer’s disease is clear unbearable strain placed on medical infrastructures, health care systems and families. Objective(s): We will present data on a number of drug discovery programs aimed at enhancing dysfunctional neurotransmitter systems in the degenerating brains of patients with AD. In addition, we will present data on antiamyloid development candidates aimed at halting the disease process. These programs span all three pillars of drug discovery, namely small molecules, vaccines and biopharmaceuticals. Methods: We have used a variety of in vitro cell based pharmacological assays using transformed cell lines to identify compounds with suitable parameters for testing in preclinical animal models. Following treatment with potential drug candidates, APP transgenic animals (Tg2576) expressing the APPsw mutation were assessed for Abeta levels using standard biochemical and neuroanatomical assays. In addition, behavioral effects on memory were measured using a contextual fear conditioning paradigm in operant chambers and novel object recognition. Freezing scores for each animal were converted to percent freezing for each portion of the test. Memory for the context (Contextual memory) for each animal was obtained by subtracting the percent freezing in the novel condition (a measure of basal activity) from S72 Symposia S4-04: Drug Discovery (Clinical Trials)