phosphorylation and release of aS were significantly decreased by APN, suggesting that APN may be antineurodegenerative. In transgenic mice expressing aS, both histopathology and move- ment disorder were significantly improved by intranasal treat- ment with globular APN when the treatment was initiated in the early stage of the disease. Conclusions: Taken together, APN may suppress neurodegeneration through modification of the metabolic pathway, and could possess a preventive therapeutic potential against not only AD but also a-synucleinopathies with dementia such as DLB. Fig. 1. Adiponectin (APN) colocalize with a -synuclein in Lewy bodies in autopsied human brain with a-synucleinopathy. Fig. 2. Effect of the recombinant adiponectin (APN) in a-synucleinopathy cell model. APN suppresses aggregation of a-syn in AdipoR I-AMPK pathway dependent manner. B103 neuroblastoma cells expressing human a-synuclein (aS) or empty vector were treated with either rec. APN (5 mg/ ml) or PBS for 24h. Cells were fractionated into TBS- : SDS- and FA-sol- uble fractions, and were analyzed by immunoblotting using anti-aS(A). In (B), cells were pre-transfected with AdipoRI siRNA or non-target (con- trol) siRNA. AMP-activated protein kinase: AMPK and p38 MAPK were activated by APN treatment (C). In (D). cells were preincubated with SB203580 (p38 MAPK inhibitor) (1 mM) or compound C (AMPK in- hibitor) (l mM). The aS phosphorylation was evaluated by immunoblotting (E) using anti-phospho-aS (paS) or anti-aS. In (F), double immunofluo- rescence confirmed that colocalization of paS with aS was reduced by APN. Proteasome activity was weakly but significantly increased by APN (G). Cells expressing aS were incubated with various PD toxins, including tunicamycin (1 mg ml) : rotenone (l00nM), and lactacystin (l mM) under serum-free conditions for 48 h (H). (mean± SEM, n¼3w5, *; P<0.05 : **; P<0.01). Fig. 3. Effect of the recombinant adiponectin (APN) in a-synucleinopathy model mice. The cells expressing human aS were incubated under serum- free conditions with globular APN (gAPN) or full-length APN (5 mg/ml) for 18 h (A). Mice were intranasally treated with either FLAG-gAPN (0.1 mg/ml 10 ml in PBS) or PBS alone. Mice brains were analyzed by immuno- histochemistry using anti-APN antibody (B). Globular APN (0.1 mg/ml, 10 ml in PBS) or PBS alone was injected into the nasal cavity of the 2-month- old aS tg mice or wild type littermates every 3 days for 3 months. The eval- uation of body weight (C) and motor performance assessed by rotarod test (D) and beam tests (E). (mean6 SEM, n¼8-9 : *; P<0.05 : **; P<0.01, ***; P<0.001). In (F). representative figures of immunohistochemistry are shown; cortex and olfactory bulb were stained with anti- paS : while thal- amus was probed with anti-aS. Insets are shown to show higher magnifica- tion of for cortex. In (G), representative figures of immunoblotting (cortex) are shown; the intensities of aS in FA fraction were quantified (mean6 SEM, n¼6 : **; P<0.01). P3-326 BLOOD-BRAIN BARRIER PERMEABLE HSP90 INHIBITOR REDUCES SOLUBLE TAU BURDEN AND RESCUES TAU-DEPENDENT PHENOTYPE IN A MOUSE MODEL OF TAUACCUMULATION John Koren, Carmen Inda, Gabriela Chiosis, Memorial Sloan Kettering, New York, NY, USA. Contact e-mail: korenj@mskcc.org Background: Current Alzheimer’s disease (AD) medications attempt to address the symptoms associated with this disorder. However, there are no FDA approved AD medications which can act on the biochemical mechanisms which drive toxic pathol- ogy including tau (MAPT, tau) accumulation. Toxic tau species are a hallmark AD pathology and are also the primary patho- genic species in a collection of neurodegenerative disorders, similar to AD, described as “tauopathies.” In these disorders, tau accumulation is associated with abnormal phosphorylation progressing to a state of hyperphosphorylation. One avenue for treatment is the inhibition of the 90kDa heat shock protein (Hsp90); a molecular chaperone found to be involved in the formation of neurotoxic species of the microtubule associated protein tau. Normally, aberrant protein accumulation is regu- lated by the molecular chaperones. However, AD presents a disease-specific population of Hsp90; a population which pre- serves disease driving tau accumulation. Methods: We present data obtained through in vivo studies utilizing a mouse model of tau accumulation (PS19, P301S tau) treated with a blood- brain barrier permeable Hsp90 inhibitor designed by our lab. Results: Hsp90 inhibition capably reduces tau species associated Poster Presentations: P3 P763