PS1 double transgenic mice

Oral O3-06: Therapeutics and Therapeutic Strategies: Novel Targets the left and right hippocampus, enthorinal cortex, and medial temporal lobe, and 3) scores of the Rey Auditory Verbal Learning test (RAVL), and ADAS subtests on memory. Multiple logistic regression analyses were performed to extract the optimal set of predictors for the separation of HC against patients with manifest AD and patients with MCI who subsequently converted to AD (N ¼ 41, mean conversion interval ¼ 1.4 yrs (SD ¼ 0.5). Results: In a first step, the best predictors among memory tests of the RAVL and ADAS were determined. The primary predictors were ADAS delayed recall, and RAVL delayed recall (30 min delay), and RAVL total immediate recall, reaching a classification accuracy of 90%. In the next step, this model was retained and additional volumetric MRI measures and CSF-measures were tested to augment prediction. In addition to the memory tests, the CSF tau/Ab ratio, left hippocampus volume and left medial temporal volume were significant predictors of MCI-AD converters vs HC, increasing the classification accuracy to 100%. When the same logistic regression equation was applied to the classification of HC against AD for validation, the sensitivity was 100% and the specificity 92.6%. Conclusions: Diagnostic accuracy of early AD is significantly augmented by the use of CSF and MRI based biomarkers and may provide an improved way of clinical diagnosis of AD. O3-05-08

RELATIONSHIP OF CEREBROSPINAL FLUID BIOMARKERS WITH IN VIVO [11C]PIB AND [18F]FDDNP BINDING

Bart N. M. van Berckel, Nelleke Tolboom, Wiesje M. van der Flier, Maqsood Yaqub, Ronald Boellaard, Nicolaas A. Verwey, Marinus A. Blankenstein, Gert Luurtsema, Albert D. Windhorst, Adriaan A. Lammertsma, Philip Scheltens, VU University Medical Center, Amsterdam, Netherlands. Contact e-mail: [email protected] Background: The purpose of this study was to investigate the relationship between cerebrospinal fluid (CSF) measurements of beta-amyloid1-42 (Aß42) and tau with both [11C]PIB and [18F]FDDNP binding in patients with Alzheimer’s disease (AD), mild cognitive impairment (MCI) and healthy controls. Methods: [11C]PIB and [18F]FDDNP scans, together with a lumbar puncture, were obtained in 38 subjects (15 AD, 13 MCI, 10 controls). Pearson’s correlations coefficients and linear regression analyses were used to evaluate potential associations between both CSF measures and global binding of both [11C]PIB and [18F]FDDNP. Results: For both [11C]PIB and [18F]FDDNP, correlations with CSF levels of Ab42 (r ¼ -0.71 and r ¼ -0.37, respectively) and tau (r ¼ 0.58 and r ¼ 0.55, respectively; all p<0.001) were found across groups. Linear regression analyses showed that, adjusted for age, sex and diagnosis, global [11C]PIB uptake had an inverse association with Ab42 CSF levels (b¼-0.50, p<0.001), whilst there was a positive association (b ¼ 0.60, p < 0.05) between global [18F]FDDNP binding and tau CSF levels. Conclusions: The inverse association between [11C]PIB and CSF Ab42 confirms the notion that [11C]PIB measures amyloid load in the brain. The positive association between [18F]FDDNP and CSF tau suggests that at least part of the specific signal of [18F]FDDNP in AD patients is due to tangles. TUESDAY, JULY 14, 2009 ORAL O3-06 THERAPEUTICS AND THERAPEUTIC STRATEGIES: NOVEL TARGETS O3-06-01

ORAL TREATMENT WITH AN Ab42 OLIGOMER MODULATING D-AMINO ACID PEPTIDE IMPROVES COGNITIVE BEHAVIOR OF APP/ PS1 DOUBLE TRANSGENIC MICE

Dieter Willbold1,2, Thomas van Groen3, Inga Kadish3, Dirk Bartnik2, Luitgard Nagel-Steger2, Olexandr Brener2, Andreas Schiffmann4, Carsten Korth4, Katja Wiesehan1, Susanne A. Funke1, 1Forschungszentrum Ju¨lich, Ju¨lich, Germany; 2Institut fu¨r Physikalische Biologie, Heinrich-

P137

Heine Universita¨t Du¨sseldorf, Du¨sseldorf, Germany; 3Dept. Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA; 4Institut fu¨r Neuropathologie, Heinrich-Heine Universita¨t Du¨sseldorf, Du¨sseldorf, Germany. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, affecting more than 20 million people world-wide. Today, only palliative therapies for AD are available. Several lines of evidence, including genetics, have provided strong evidence for a central role of amyloid-b-peptide (Ab) in the pathogenesis of AD. Recents studies indicate that soluble Ab oligomers instead of fibrillar forms are the major toxic species. Methods: We successfully tested Ab binding D-peptides in AD transgenic mouse models regarding their therapeutic properties. Additionally, we used several biophysical methods for the elucidation of the mechanism thereof. Results: We report on a novel D-enantiomeric amino acid peptide which reduces amyloid plaque load and cerebral damage of transgenic mouse models of AD after direct brain application. Additionally, we show that next to plaque load and inflammation reduction, oral application of the peptide improves cognitive performance. We are providing in vitro data suggesting an Ab42 oligomer modulating activity of D3. Conclusions: The D-enantiomeric peptide D3 is able to modulate Ab42 oligomers in vitro. Regardless of its in vivo mechanism of action, D3 exerts therapeutically interesting activities. O3-06-02

TOLL-LIKE RECEPTOR 9 LIGAND CPG ODN AS A NEW HIGHLY EFFECTIVE AGENT FOR PREVENTION AND/OR TREATMENT OF ALZHEIMER’S DISEASE

Henrieta Scholtzova1, Richard J. Kascsak2, Kristyn A. Bates3, Allal Boutajangout4, Daniel J. Kerr2, Harry C. Meeker2, Pankaj D. Mehta2, Daryl S. Spinner2, Thomas Wisniewski1,5, 1NYU School of Medicine, Department of Neurology, New York, NY, USA; 2New York State Institute for Basic Research in Developmental Disabilities, New York, NY, USA; 3School of Exercise, Biomedical and Health Science, Edith Cowan University, Joondalup, Australia; 4NYU School of Medicine, Department of Psychiatry, New York, NY, USA; 5NYU School of Medicine, Department of Pathology, New York, NY, USA. Contact e-mail: [email protected] Background: Manipulation of the immune system is becoming a promising treatment approach for Alzheimer’s disease (AD). However, when this approach was tried in humans, in contrast to results in AD animal models, encephalitis emerged as a significant form of toxicity in some patients. Vaccination studies have so far mainly targeted the adaptive immune system. Our research group postulated stimulation of the innate immune system as possible alternative method for ameliorating AD related pathology, without associated toxicity. Our prior work in prion disease, suggested that this could be done effectively via Toll-like receptor 9 (TLR9). Objective: To assess the utility of TLR 9 agonist CpG ODN to stimulate the innate immune system and prevent AD pathology in a mouse model. Methods: Female Tg2576 mice were injected with either the TLR9 agonist type B CpG oligodeoxynucleotide 1826 or vehicle beginning at 6 weeks of age, and once a month thereafter for a total of 14 injections. Controls were non-transgenic C57BL/6 x SJL mice injected with vehicle on the same schedule. At the age of sixteen months, the mice were subjected to behavioral testing. Results: No difference between Tg groups was found in any of the locomotor parameters. CpG treatment led to working memory improvement in APP Tg2576 mice as indicated by radial arm maze testing (two-way ANOVA p ¼ 0.019, post-hoc Tg-CpG vs Tg-vehicle, p ¼ 0.026). In evaluating the efficacy of CpG ODN peripheral administration in AD mice, we found that stimulation of TLR9 signaling led to 66%(p ¼ 0.0001) reduction in cortical and 59% (p ¼ 0.002) reduction in hippocampal amyloid burden compared to vehicle treated Tg animals. This remarkable reduction of amyloid burden was paralleled by a reduction in the numbers of activated microglia and astrocytes. When analyzed separately, we observed a significant decrease in vascular amyloid burden without any evidence of increased cerebral microhemmorhages. Furthermore, treatment with CpG ODN was highly effective at reducing the brain Ab