Symposium

Symposium 30 Frontiers in brain ageing シンポジウム30 神経老化に関する最近のトピックス

SY30-1 Oral diseases and Alzheimer's disease 口腔疾患とアルツハイマー病分子病態 Michikawa Makoto（道川誠） Nagoya City University, Graduate School of Medical Sciences There are many studies suggesting a link between periodontists and teeth loss, and dementia. However, the cause and result relationship between these remain undetermined. We have performed studies to clarify the relationship between periodontists and Alzheimer’s disease, tooth removal and dementia, and soft diet and dementia using APP-tg mice (Alzheimer’s disease model mouse). We found that inflammation occurring in periodontists invades into the brain region and enhances Aβ deposition and memory impairment. Whereas, teeth loss and soft diet induced dementia accompanied by impaired BDNF signaling and hippocampal neuronal loss without enhancing Alzheimer’s anthologies.		SY30-2 Mechanism of signal transduction of TREM2, an Alzheimer's disease risk factor expressed on microglia ミクログリアに発現するアルツハイマー病危険因子TREM2の細胞内シグナリング機構の解析 Shirotani Keiro（城谷圭朗），岩田修永 Dep. of Genome-based Drug Discovery, Nagasaki University Genome-wide analysis has identified TREM2 (triggering receptor expressed on myeloid cells 2), which is abundantly expressed on microglia in brain, as one of the strongest risk factors of Alzheimer’s disease as well as the other neurodegenerative disorders. TREM2 is a single-pass transmembrane protein associated with DAP12 (DNAX-activating protein of 12 kD) which contains ITAM (immunoreceptor tyrosine-based activation motif) in the cytoplasmic domain and transduces signals from extracellular ligands which regulate phagocytosis and inflammatory cytokine productions. However TREM2 ligands which accelerate the disease progression and the signaling mechanisms are unclear. We have established sensitive reporter systems of TREM2 signaling and are analyzing the underlying mechanisms. Our recent data will be updated in the symposium.

SY30-3 Accumulated oxidative injury in neuronal ageing and Parkinson disease 老化に伴う酸化ストレス傷害の蓄積とパーキンソン病 Maruyama Wakako（丸山和佳子） Dept Health and Nutrition, Faculty of Psycol. Physl. Sci., Aichi Gakuin Univ. Recently, toxic alpha-synuclein (aS) oligomer, which can mediate cell-to-cell propagation is suggested to cause sporadic Parkinson disease. aS interacts with membrane lipids especially polyunsaturated fatty acids to stabilize its three-dementional structure. Peroxidation of polyunsaturated fatty acids may reduce their affinity to aS and on the other hand, peroxidation byproducts might modify aS. 4-Hydroxy-2-nonenal (4HNE) derived from n-6 polyunsaturated fatty acids was reported to modify aS to produce a toxic oligomer. Moreover, the accumulation of 4HNE was found in parkinsonian brains. Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acids abundant in the neuronal membrane, was also found to enhance aS oligomerization; however, the precise details of the chemical reaction involved are unclear. Propanoylated lysine (PRL), a specific indicator of docosahexaenoic acid oxidation, was increased in neuronal differentiated human neuroblastoma SH-SY5Y cells overexpressing aS (Syn-SH cells). In Syn-SH cells, lysosome activity was reduced and macroautophagy activity was compensatory increased. A lysosome inhibitor chloroquine induced aS aggregation in the cytoplasm in Syn-SH cells. Aggregated aS was found to be modified by PRL. DHA promoted aS polymerization, which was modified by PRL in vitro. aS may function as a scavenger of lipid radicals and as a result, modified aS is continuously produced in the neurons. Decreased activity of macroautophagy in ageing and PD may be responsible for neuronal death by reduced degradation of toxic aS oligomer modified by lipid radicals. Biphasic function of aS is discussed.		SY30-4 Intranasal rifampicin: Development of anti-dementia drugs with anti-inflammatory action 経鼻投与リファンピシン：抗炎症作用を持つ抗認知症薬の開発 Tomiyama Takami（富山貴美）¹，梅田知宙¹，田中晶子²，酒井亜由美¹，山本昌²，坂根稔康³ ¹Department of Translational Neuroscience, Osaka City University Graduate School of Medicine ²Kyoto Pharmaceutical University ³Kobe Pharmaceutical University Cerebral accumulation of amyloid oligomers is believed to be the initial step in the pathogenesis of neurodegenerative dementia such as Alzheimer’s disease and tauopathy. Accordingly, reducing the content of amyloid oligomers has been hypothesized as a rational strategy to treat these diseases. Previously, we demonstrated that oral rifampicin significantly reduced the levels of Aβ and tau oligomers and improved memory in mice. In addition, rifampicin has been shown to possess radical-scavenging ability, which may also contribute to neuroprotection against the toxicity of reactive oxygen species generation that increases in neurodegenerative disorders. Despite these beneficial effects, rifampicin is known to have occasional, non-negligible adverse effects such as liver injury and drug-drug interactions, which discourages the use of rifampicin for a long period. To explore safer rifampicin treatment, APPOSK mice, a model of Alzheimer’s disease, were treated with rifampicin for 1 month via oral, intranasal, and subcutaneous administration, and their therapeutic efficacy and safety were compared. Intranasal or subcutaneous administration of rifampicin improved memory more effectively than oral administration. The improvement of memory was accompanied with the reduction of neuropathologies including Aβ oligomer accumulation, tau abnormal phosphorylation, and synapse loss. Serum levels of a liver enzyme significantly rose only by oral administration. Pharmacokinetic study revealed that the level of rifampicin in the brain was highest with intranasal administration. Considering its easiness and non-invasiveness, intranasal administration would be the best way for long-term dosing of rifampicin. Our findings provide a novel approach to the prevention of dementia.

SY30-5 Brain aging and alteration of biopterin metabolism in Parkinson's disease パーキンソン病におけるビオプテリン代謝変化と神経老化との関係 Ichinose Hiroshi（一瀬宏）¹，荒川志信¹，渡邊祐貴¹，黒崎宏貴¹，Aasly Jan² ¹School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan ²Department of Neurology, St.Olavs Hospital, Norwegian University of Science and Technology (NTNU), Trondheim, Norway Parkinson’s disease is an age-associated neurodegenerative disease, and the aging process should be deeply involved in the etiology. An increasing number of evidence suggest that low-level chronic inflammation, termed sterile inflammation or inflammaging, is crossly correlated with aging. Chronic stress or inflammation increases tryptophan metabolism along the kynurenine pathway. Recently a metabolite of the kynurenin pathway, xanthurenic acid, was reported to be a strong inhibitor for the third step of tetrahydrobiopterin (BH4)-biosynthesis catalyzed by sepiapterin reductase (Haruki et al. J Biol Chem 2016). BH4 is essential for biosynthesis of monoamine neurotransmitters, i.e. dopamine, noradrenaline, and serotonin; and neopterin is an intermittent metabolite of BH4-biosynthesis, which is known to increase with activation of cellular immunity. We quantitated the BH4 and neopterin contents in the CSFs of patients with sporadic Parkinson’s disease (sPD), LRRK2-mutation carriers and patients, and individuals without neurodegenerative disorders (non-PD). We found that the BH4 levels were negatively correlated with age in the CSF of the non-PD individuals. The neopterin/biopterin ratios in the CSF were positively correlated with the severity of PD symptoms assessed by UPDRS-III. Furthermore, the neopterin levels in the LRRK2 patients were significantly increased compared with those of non-PD and sPD individuals. These data suggest that the increased inflammation in the brain of PD patients might be involved in the etiology and progression of PD.