神経化学
ISN/JSNジョイントシンポジウム
女性研究者が先導するアルツハイマー病の神経化学研究 |
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| 7月7日（金） 16:00-18:00 Room B
2SY⑦-1
Diosgeninによるアルツハイマー病の記憶改善～軸索再投射メカニズムの解明と臨床研究での検証～
Diosgenin improves memory in Alzheimer's disease - Axonal reprojection mechanism and validation in clinical studies
東田 千尋
富山大学 和漢医薬学総合研究所 神経機能学領域
Chihiro Tohda
Section of Neuromedical Science, Inst. of Natural Med, Univ. of Toyama, Toyama, Japan
In Alzheimer's disease (AD), repairing neuronal circuits is very crucial to improve memory impairment. We had focused on diosgenin, which is known as a constituent of Yam (rhizome of Dioscorea japonica or D. batatas). Our studies provided solid evidence showing that administration of diosgenin to AD model mice (5XFAD) restored memory impairment. To figure out its mechanism, axon-growing neurons in the hippocampus connecting to the prefrontal cortex were selectively visualized. Diosgenin (p.o.) extended damaged axons successfully to the prefrontal cortex. The axon-growing hippocampal neurons and naive neurons were captured by laser microdissection to serve DNA microarray. The two genes with the largest increases in expression (SPARC and Gal-1) in axon-growing neurons were focused. Overexpression of them in hippocampal neurons improved memory deficits and promoted axonal reinnervation. Effects of diosgenin in humans were evaluated. We optioned to perform clinical studies with Yam extract as more realistic and feasible approaches than those with diosgenin itself. A randomized, double blinded, crossover clinical study for healthy subjects clarified upregulation of cognitive function by taking Yam extract for 12 weeks. Furthermore, a specified clinical trial was conducted on subjects with mild cognitive impairment and mild AD. | | 7月7日（金） 16:00-18:00 Room B
2SY⑦-2
タウによる神経変性のメカニズム：タウはどのように毒性を獲得するのか？
Mechanisms underlying tau-induced neurodegeneration: how do tau proteins become toxic?
安藤 香奈絵
東京都立大学 理学部 生命科学科
Kanae Ando
Dept. of Biol. Sci., Tokyo Metropolitan University, Tokyo, Japan
Abnormal accumulation of the microtubule-binding protein tau is believed to cause neuron loss in Alzheimer’s disease and related neurodegenerative diseases. Tau in healthy neurons distribute to the axons and regulates microtubule stability, while in disease conditions, it is misfolded and accumulated in the cytosol. However, what changes in disease pathogenesis cause tau abnormality is not fully understood. Using Drosophila as a powerful model system to understand human diseases, we found that post-translational modifications of tau, specifically its phosphorylation in the microtubule-binding repeats, play an initiating role in tau accumulation. Tau phosphorylation at these sites is mediated by MARK4, a member of an evolutionarily conserved kinase family Par-1. MARK4 is activated in response to age-related changes, such as disruption of axonal transport of mitochondria and metabolism. In addition to tau phosphorylation, our data suggest that MARK4 triggers pathogenic conformational changes of tau via liquid-liquid phase separation. Our results suggest that dysregulation of MARK4 activity is the critical step in the cascade of events leading to neurodegeneration in disease pathogenesis. | | 7月7日（金） 16:00-18:00 Room B
2SY⑦-3
Cholinergic signaling: relevance to cognition and Alzheimer’s disease
F. Prado Vania
University of Western Ontario, Robarts Research Institute, Department of Anatomy and Cell Biology, Department of Physiology and Pharmacology
Basal forebrain cholinergic neurons are among the most vulnerable cell populations to Alzheimer’s disease (AD). However, the precise relationship between decreased cholinergic function and behavioral manifestations in AD is poorly understood. To address this issue, we have developed several mouse models of cholinergic deficiency by genetically-targeting the vesicular acetylcholine transporter (VAChT), the protein responsible for loading synaptic vesicles with acetylcholine. We showed that, forebrain cholinergic failure alters multiple molecular pathways in the hippocampus, likely through global changes in the transcriptome, accelerates age-dependent AD-like pathology, and leads to deficits in memory, attention and behavioral flexibility. We also investigated the impact of biological sex on cholinergic function and amyloid pathology using a cross-species translational strategy in mouse models and older adult humans. A causal relationship between VAChT levels and amyloid pathology was found in male but not in intact female mice. Ovariectomy restored this relationship in female mice. In humans, cholinergic dysfunction worsened amyloid pathology similarly in males and postmenopausal females. This work highlights the need to understand further the relationship between sex hormones, cholinergic function and translation of results between female mice and humans.
Acknowledgements: Supported by CIHR, NSERC, BrainsCAN, Alzheimer’s Society of Canada. | | 7月7日（金） 16:00-18:00 Room B
2SY⑦-4
Distinct RNA regulators of acetylcholine signaling in men and women living with brain diseases
Soreq Hermona
The Edmond and Lily Safra Center of Brain Science at the Hebrew University of Jerusalem, Israel
Regulators of coding transcripts of acetylcholine (ACh) functioning in the human brain include microRNAs (CholinomiRs) suppressing cholinergic-related mRNAs by targeting the ACh-related genes (e. g. miR-132). CholinomiRs may supervise AChblocked inflammation; impose metabolic impact, and regulate neuronal functioning. However, recruiting them may be less rapid and effective than desired. A ‘changing of the guards’ process is enabled by nuclease-driven increases of cholinergictargeted Transfer RNA (tRNA) fragments (CholinotRFs) that exist in all cells, and may be produced from either the nuclear or the mitochondrial genome to rapidly operate like miRs. Recently, we discovered striking differences in brain CholinomiR and CholinotRF profiles between men and women, which may affect the pace and severity of mental diseases as well as responses to therapeutics to those diseases between men and women patients. Furthermore, we discovered acute decline of mitochondrial-originated CholinotRFs in the nucleus accumbens of women living with Alzheimer’s disease, in whom this depletion reflects their rapid cognitive deterioration for which there was no explanation beforehand. The implications for the future may involve both diagnostic and RNA-therapeutic efforts to ensure dynamic regulation of such small non-coding RNAs in health and disease, in a sex- and age-related manner. | |
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