PT583. Long-term Effect of Yokukansankachimpihange on Motivation in wild-type mice

Granulin (GRN) mutations were identified in patients with familial frontotemporal lobar degeneration (FTLD) with ubiquitin pathology in 2006 studies. GRN transcript haploinsufficiency has been proposed as a disease mechanism that leads to the loss of functional progranulin (PGRN) protein. GRN mutations were first found in tau-negative FTLD patients, however, recent findings indicate that these mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer’s disease and corticobasal degeneration. Moreover, PGRN reduction in tau transgenic mice is associated with increasing tau phosphorylation and accumulation. To investigate the influence of a decline in PGRN protein on other forms of neurodegenerative-related protein accumulation, four human GRN mutation cases (age at death; 54, 55, 56 and 78 years old) were investigated by histochemical and biochemical analyses. The results showed neuronal and glial tau accumulation in all cases analyzed. Massive neuronal tau staining revealed pretangle forms and glial tau in both astrocytes and oligodendrocytes. Furthermore, phosphorylated α-synuclein-positive structures were also found in oligodendrocytes and the neuropil. Immunoblot analysis of fresh frozen brain tissues revealed that tau protein was present in the sarkosyl-insoluble fraction, which was composed of threeand four-repeat tau isoforms, resembling Alzheimer’s disease. Our data suggest that PGRN reduction might be the cause of neuronoglial multiple proteinopathies, including TDP-43 proteinopathy, tauopathy and α-synucleinopathy, due to the accelerating accumulation of abnormal proteins. PT582 Myristic Acid Hitchhiking on Sigma-1 Receptor to Fend Off Neurodegeneration Shang-Yi Tsai, Jenna Ciesielski, Tsung-Ping Su Cellular Pathobiology Section, Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, Baltimore, Maryland 21224, U.S.A. Abstract Neurodegenerative diseases are linked to tauopathy as a result of cyclin dependent kinase 5 (cdk5) binding to its p25 activator instead of its p35 activator and becoming over-activated. The overactive complex stimulates the hyperphosphorylation of tau proteins, leading to neurofibrillary tangles (NFTs) and stunting axon growth and development. It is known that the sigma-1 receptor (Sig-1R), an endoplasmic reticulum chaperone, is involved in axon growth by promoting neurite sprouting through nerve growth factor (NGF) and tropomyosin receptor kinase B (TrkB). It has also been previously demonstrated that a Sig-1R deficiency impairs the process of neurogenesis by causing a down-regulation of N-methyl-D-aspartate receptors (NMDArs). The study sought to understand the relationship between Sig-1R and tauopathy. It was discovered that the Sig-1R helps maintain proper tau phosphorylation and axon development by facilitating p35 myristoylation and promoting p35 turnover. Neurons that had the Sig-1R knocked down exhibited shortened axons and higher levels of phosphorylated tau proteins compared to control neurons. Here we discuss these recent findings on the role of Sig-1R in tauopathy and highlight the newly presented physiological consequences of the Sig-1R-lipid interaction, helping to understand the close relationship between lipids and neurodegeneration. PT583 Long-term Effect of Yokukansankachimpihange on Motivation in wild-type mice Takuya Hamaguchi1, Iku Tsutsui-Kimura2, Marina Tsukamoto2, Masaru Mimura2, Kenji F. Tanaka2 1Center for Kampo Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160–8582, Japan 2Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160–8582, Japan Abstract Backgrounds and Objectives: Apathy is the loss of motivation, and coincides with 60% of patients with Alzheimer’s disease. The establishment of effective treatments for refractory apathy condition is required. Here we addressed the potentials of treating apathy using Kampo medicine. To pursue this issue, we established the behavioral experiment, which was optimized toBackgrounds and Objectives: Apathy is the loss of motivation, and coincides with 60% of patients with Alzheimer’s disease. The establishment of effective treatments for refractory apathy condition is required. Here we addressed the potentials of treating apathy using Kampo medicine. To pursue this issue, we established the behavioral experiment, which was optimized to the long-term Kampo medication. We examined the long-term (over 6 months) effect of Yokukansankachimpihange (YKSCH), one of the Kampo formulae, on motivation in the instrumental task using wild type mice. Methods: C57BL/6J mice were divided into two groups: YKSCHcontaining chow and normal chow was administered. Mice were initially trained to press the lever to earn palatable food reward on a fixed ratio (FR) reinforcement schedule, then trained in a progressive ratio (PR) reinforcement schedule. The final ratio completed represented the break point (BP) and that was recognized as an index of instrumental motivation. YKSCH administration started at the beginning of the FR session. We examined the BP of both group until 40 weeks of age. Results: We first tested whether two sessions per week was enough to maintain the acquired PR performance. Daily PR session was required to evaluate the short-term effect of western medicine, but daily session was laborious in the long-term evaluation of Kampo medication. We optimized the PR task parameter, and confirmed that the modified PR schedule that was conducted twice a week was able to maintain task performance over 6 months.