S4–04–06: Thiadiazolidindiones, selective glycogen synthase kinase–3 inhibitors as potential therapeutic agents for Alzheimer's disease and other tauopathies

not available. S4-04-06 THIADIAZOLIDINDIONES, SELECTIVE GLYCOGEN SYNTHASE KINASE-3 INHIBITORS AS POTENTIAL THERAPEUTIC AGENTS FOR ALZHEIMER’S DISEASE AND OTHER TAUOPATHIES Ana Martinez, Neuropharma, Madrid, Spain. Contact e-mail: amartinez@neuropharma.es GSK-3 is a serine/threonine kinase with an astoundingly diverse number of actions in intracellular signalling systems. It plays crucial roles in several human diseases having great potential for therapeutic intervention. Currently, GSK-3 inhibitors arise as promising drugs for the pharmacotherapy of several acute pathologies as cancer, diabetes, stroke, mood disorders, inflammation or Alzheimer s disease (AD), among others. Recently, a large body of evidence has accumulated linking GSK-3 with tau hyperphosphorylation, and more recently, A production, the two pathological hallmarks of AD. The small heterocyclic thiadiazolidindiones (TDZDs) represent the first non-ATP competitive GSK3 inhibitors reported to date and have been proposed as new disease-modifying agents for the effective treatment of neurodegenerative disorders where tau phosphorylation plays a key role, such as AD. TDZDs have favourable ADME-Tox drugable properties and their therapeutic potential has been proved using different animal models. A prolonged oral administration of a TDZD compound to the GSK3 conditional transgenic mice (Tet/GSK3 ) produces a significant decrease on tau phosphorylation both in the hippocampus and cortex areas where the transgene is expressed. Moreover, this TDZD compound is able to improve cognition (by object recognition test), and diminish the cortex and hippocampus amyloid plaque load in an APP-PS1 double transgenic mouse after 2 months of oral administration. The positive observed effects in these studies together with some other neuroprotective properties found on this family of compounds, confirm the potential of TDZDs as new therapeutic agents for the inhibition of GSK3 and tau phosphorylation in AD and other tauopathies. WEDNESDAY, JULY 19, 2006 ORAL O4-01 DISEASE MECHANISMS (APOE) O4-01-01 THE INFLUENCE OF AD FAMILY HISTORY AND APOE4 ON VULNERABLE BRAIN REGIONS IN COGNITIVELY NORMAL MIDDLE-AGED ADULTS Sterling C. Johnson, Taylor W. Schmitz, Michele L. Ries, Mehul A. Trivedi, Craig S. Atwood, Cynthia M. Carlsson, Sanjay Asthana, Mark A. Sager, University of Wisconsin, Madison, WI, USA; VA Hospital, Madison, WI, USA. Contact e-mail: scj@medicine.wisc.edu Background: First-degree family history of sporadic Alzheimer Disease (AD) and the apolipoprotein E e4 (APOE4) are risk factors for developing AD. Although the role of APOE4 in the pathogenesis has been well studied, family history remains a rarely studied and poorly understood risk factor. Objective(s): To determine the relative contribution of APOE4 and family history of AD on brain function. Methods: We examined 68 middle-aged participants with a parent diagnosed with AD ( FH) and 64 age-, genderand education-matched controls without a first-degree family history of any dementia (–FH). All underwent cognitive testing, ApoE genotyping and performed two distinct functional MRI (fMRI) tasks. One of the tasks required discrimination of novel items from previously learned items and has previously been shown to activate the hippocampus in healthy adults. The second task was a self-referential decision making task and has previously been shown to activate the posterior cingulate in healthy adults. For each task, a 2 2 factorial ANOVA (presence/absence of parental family history and presence/absence of the APOE4) was used to detect group effects. Results and Conclusions: A greater response to novel items was detected in the mesial temporal lobe and fusiform gyrus bilaterally among persons without a first-degree family history of AD. In hippocampal areas, the –FH e4 carriers exhibited the greatest signal change, and the FH e4 carriers the least. For the self-referential task, there was a main effect of family history in the posterior cingulate, where a greater response was observed for persons without a family history of AD. There was no main effect of APOE in this young cohort. FH of AD was a strong predictor of the neural response on these tasks in regions known to be vulnerable to AD. Further, in appears that FH is modulating the effect of APOE in these middle-aged adults, suggesting that an as yet unspecified factor embodied in first-degree family history of AD is influencing the expression of APOE4 on brain function. O4-01-02 THE EFFECT OF APOE-4 ON FMRI DEACTIVATION IN OLDER CONTROLS, MCI SUBJECTS AND AD PATIENTS Maija Pihlajamaki, Saul M. Miller, Kristina M. DePeau, Kim A. Celone, Lars Bertram, Rudolph E. Tanzi, Bradford C. Dickerson, Marilyn S. Albert, Deborah Blacker, Reisa A. Sperling, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland; Departments of Neurology/Psychiatry/Radiology/Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Contact e-mail: mpihlajamaki@rics.bwh.harvard.edu Background: The epsilon 4 allele of apolipoprotein E (APOE-4) is a known risk factor for Alzheimer’s disease (AD). PET studies of nondemented APOE-4 carriers have revealed hypometabolism of posterior association cortices, particularly in posterior cingulate and parietal regions, similar to the pattern of metabolic abnormalities seen in AD patients. A similar set of regions have shown alterations in deactivation, or “default mode activity”, in fMRI studies of AD patients. Objective: We wanted to investigate the effect of APOE-4 on fMRI deactivation pattern in aging, MCI and early AD. Methods: A total of 82 older subjects underwent fMRI during a face-name associative encoding paradigm. At least one APOE-4 allele was present in 8/29 (28%) of older controls (OC), in 13/38 (34%) of subjects with mild cognitive impairment (MCI, defined here as CDR 0.5), and in 9/15 (60%) of patients with early AD. fMRI was performed using a 3.0T scanner, oblique coronal acquisition, and spatial resolution of 3.125 3.125 6 mm. Data were analyzed using FEAT5.43 software contrasting the passive fixation baseline to the encoding novel and repeated face-name pairs; peak z-values and corresponding uncorrected p-values for the within and between-group comparisons are reported. Results: The OC group demonstrated significant deactivation in posterior cingulate/retrosplenial, and precuneal regions (corresponding to Brodmann areas 23/29/ 30/31; z 4.83, p 0.0001). OC APOE-4 carriers showed less deactivation S74 Oral O4-01: Disease Mechanisms (APOE)