therapy, not only for the treatment of AD but also for other Tau-mediated neurodegenerative diseases. P2-388 17-BETA-ESTRADIOL: A POTENTIAL THERAPEUTIC DRUG FOR ALZHEIMER’S DISEASE Pardeep Kumar, R. K. Kale, Najma Baquer, Jawaharlal Nehru University, New Delhi, India. Background: Alzheimer’s disease (AD) is the most common form of de- mentia in the elderly. AD is characterized by the presence of amyloid pla- ques which are formed from deposits of b-amyloid protein (Ab). Accumulation of oligomeric Ab in the brain contributes to neuronal dys- function and ultimately leads to neurodegeneration. During aging the brain experiences structural, molecular, and functional alterations. These changes increase during menopausal condition in females when the level of estradiol is decreased. Recently, there has been a growing interest in the action and functions of the ovarian steroid hormone estradiol, particularly on whether they are neuroprotective for such age related disease and neurodegenerative conditions like stroke, Parkinson’s disease and AD. The objective of this study was to investigate protective potential of 17b estradiol (E2) treatment on the activity of monoamine oxidase, calcium homeostasis, membrane po- larization, genomic DNA degradation, 4- hydroxynonenal and protein oxi- dation levels occurring in brains of female rats of 3 months (young), 12 months (adult) and 24 months (old) age groups, and to see whether these changes are restored to normal levels after exogenous administration of es- tradiol. Methods: The aged rats (12 and 24 months old) (n ¼ 8 for each group) were given subcutaneous injection of 17 b -estradiol (0.1 mg/g body weight) daily for one month. After 30 days of hormone treatment, ex- perimental animals of all the groups were sacrificed and brains were isolated for further study. Results: The results obtained in the present work revealed that normal aging was associated with significant increases in the activity of monoamine oxidase, calcium homeostasis, genomic DNA degradation, 4- hydroxynonenal and protein oxidation levels in the brains of aging female rats, and a decrease in membrane polarization. Our data showed that exog- enous administration of E2 brought these changes to near normalcy in aging female rats. Conclusions: It can therefore be concluded that E2’s beneficial effects seemed to arise from its, antioxidant and antilipid peroxidative ef- fects, implying a therapeutic potential drug for age related changes. Based on our studies and others, we conclude that E2 have therapeutic potential for adjunctive therapy along with dopamine replacement in AD. P2-389 SUVN-D1104010: NOVEL 5-HT4 RECEPTOR PARTIAL AGONIST FORTHE TREATMENT OF ALZHEIMER’S DISEASE Ramakrishna Nirogi, Pradeep Jayarajan, Vishwottam Kandikere, Medapati Rajesh Babu, Vijay Benade, Grandhi V. Ramalingayya, Lakshmi Narayana Manjunath, Ranjithkumar Ponnamaneni, Mohammed Abdul Rasheed, Mohamad Sadik Mulla, Suresh Yarlagadda, Ravella Srinivasa Rao, Suven Life Sciences Ltd, Hyderabad, India. Background: The need for improved Alzheimer’s disease therapies is un- met. 5-HT 4 receptor may play a role in memory and learning. Activation of 5-HT 4 receptors has been reported to modulate acetylcholine release and reduce beta amyloid accumulation. It is postulated that activation of 5-HT 4 receptors will offer improved clinical efficacy and/or tolerability rel- ative to acetylcholine esterase inhibitors. 5-HT 4 receptor partial agonists may be of benefit for both the symptomatic and disease-modifying treatment of cognitive disorders. Methods: SUVN-D1104010 a potent and selective 5-HT 4 receptor partial agonist was evaluated for its procognitive property in object recognition task and radial arm maze task using rats. Modulation of acetylcholine levels by SUVN-D1104010 was evaluated using brain micro- dialysis technique. Results: SUVN-D1104010 reversed the episodic mem- ory deficits in object recognition task and working memory deficits induced by scopolamine in radial arm maze task. Oral administration of SUVN- D1104010 significantly increased the brain acetylcholine levels. The effect observed was blocked by a selective 5-HT 4 antagonist. Conclusions: SUVN-D1104010 is a potent, selective, orally bioavailable and efficacious 5-HT 4 receptor partial agonist that holds promise for the management of the hallmark symptomatologies observed in Alzheimer’s disease. P2-390 EMERGING RELATIONSHIP BETWEEN DEVELOPMENT AND DEGENERATION: TRKA- APP INTERACTION AS ATHERAPEUTIC TARGET IN ALZHEIMER’S DISEASE Qiang Zhang, Olivier Descamps, Matthew Hart, Karen Poksay, Patricia Spilman, Olivia Gorostiza, Varghese John, Dale Bredesen, Buck Institute for Research on Aging, Novato, California, United States. Background: It has been proposed that disrupted retrograde transport of NGF-TrkA complexes underlies basal forebrain cholinergic neuron (BFCN) degeneration in Alzheimer’s disease (AD). Indeed, targeted BFCN delivery of NGF has been found promising in AD treatment and is currently in a phase II clinical trial. The prevailing view of Alzheimer’s dis- ease (AD) is that amyloid-beta (Abeta) causes toxicity through chemical and physical mechanisms. Our data suggest that Abeta functions physiologically as an anti-trophin, and Abeta binding to APP induces APP processing to multiple peptides that mediate physiological neurite retraction and synaptic reorganization (Nat Med 6:397; PNAS 103:7130). Methods: An unbiased screen for compounds that block APP caspase cleavage identified ADDN1351, which reduced APP-C31 by 90%. Surprisingly, ADDN1351 proved to be a TrkA inhibitor. We then evaluated the effect of TrkA over-ex- pression on APP-C31 production and cell death induction through transfec- tion, Western blots and MTTassays. We also studied the interaction between APP and TrkA through co-immunoprecipitation and APP-Gal4 transactiva- tion. Furthermore, we treated PDAPP transgenic mice with TrkA inhibitor GW441756 (10mg/kg, 5 days) and assayed the levels of Abeta and sAPPal- pha through ELISA and AlphaLISA. Results: TrkA over-expression in- creased APP-C31 and cell death. APP-C31 cleavage did not occur with the kinase-dead TrkA mutant or in the presence of TrkA inhibitor GW441756, whereas induction was enhanced by NGF. TrkA was shown to interact with APP in co-immunoprecipitation. In APP-Gal4 transactiva- tion assays, TrkA inhibited the transactivation directed by Fe65 or Mint3/ YAP by over 90%. Moreover, treatment of PDAPP transgenic mice with GW441756 not only decreased Abeta, but also increased sAPPalpha. Conclusions: These results suggest TrkA inhibition-rather than NGF activa- tion-as a novel therapeutic approach, and raise the possibility that such an approach may counteract the hyperactive signaling resulting from the accu- mulation of active NGF-TrkA complexes due to reduced retrograde trans- port. The results also suggest that the optimal therapy for AD may involve both the delivery of NGF or NGF mimetics to basal forebrain cho- linergic neuron somata and a TrkA inhibitor that is active more distally. P2-391 HUMAN NEURAL STEM CELL TRANSPLANTATION RESULTS IN MEMORY IMPROVEMENT IN A 3XTG ALZHEIMER’S DISEASE MODEL MICE Rahasson Ager, Mathew Blurton-Jones, Joy Davis, Andranik Agazaryan, Frank LaFerla, University of California, Irvine, Irvine, California, United States. Background: Alzheimer’s disease (AD) is the most prevalent cause of de- mentia globally and poses an overbearing financial burden upon the health- care system of many nations. While currently affecting around 35 million people worldwide, the disease is predicted to more than double over the next two decades with an estimated financial cost of well over half a trillion dollars. Unfortunately, current therapeutics provides no disease altering ef- fects leaving the demand for novel therapies high. Cell replacement therapy is increasingly being investigated as a potential treatment for neurological disorders and injury. Studies using transgenic and non-transgenic rodent models of central nervous system disorders including, stroke, spinal cord in- jury and Parkinson’s disease, have demonstrated positive results using stem cell transplantation, which has been demonstrated to be dependent on mul- tiple mechanisms of action. Methods: Our lab has previously shown that Poster Presentations: P2 P399