Wakate Dojo
Disorders of Nervous System 3
若手道場口演
神経系の疾患3 |
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| 7月26日（金）8:30～8:50 第10会場（万代島ビル 6F 会議室）
2WD10bm1-1
Diosgeninによる脳内の軸索再伸長を介したアルツハイマー病の記憶改善作用
Ximeng Yang（楊 熙蒙），Chihiro Tohda（東田 千尋）
富山大 和漢医薬学総合研究所 神経機能学分野
Alzheimer's disease (AD) is a progressing neurodegenerative disorder developed by deposition of Aβ in the brain. Since neural networks in the brain had already been severely disrupted when be diagnosed, it is important to restore neural circuits for recovery of memory function in AD. We previously found that diosgenin, a constituent of Dioscorea Rhizoma, restored Aβ-induced axonal atrophy in neurons (in vitro) and improved memory function in a mouse model of AD, 5XFAD. Although no studies have demonstrated that degenerated axons regrow again toward their native target in AD brains, we hypothesized that proper circuits would be reconstructed by diosgenin in AD brain. Therefore, in this study, we investigated whether diosgenin promotes proper axonal regrowth in 5XFAD brains, and clarify the mechanisms for accurate pathfinding of axons in adult injured brains.
At first, axonal regrowth effect of diosgenin in vivo was investigated using cortex-axotomized mice. Oral administration of diosgenin for 15 days significantly promoted axonal regrowth in the axotomized brain area. Next, we focused on a long distance axonal projection in the circuit for memory formation; the hippocampus to the prefrontal cortex. Retrograde tracing revealed that axonal projections from the hippocampus to the prefrontal cortex significantly decreased in 5XFAD compared to wild-type mice. However, 14-day administration of diosgenin to 5XFAD mice significantly increased axonal projections in this circuit. At this time, object recognition memory of 5XFAD mice was significantly improved by diosgenin administration. After that, naïve neurons and axon-regrew neurons in the brain were captured by laser microdissection to perform DNA microarray. We are now trying to clarify the mechanisms of regrowth of axons and their reconnection to native target neurons in AD brains.
Our study suggests for the first time that degenerated axons in AD brains have capacities to regrow toward their native target neurons. Furthermore, diosgenin may be a promising drug to remodel neural circuits by promoting axonal regrowth and recover memory function in AD. This finding shows the plasticity of injured axons in adult brains, and proposes a novel therapeutic strategy to promote axonal regrowth for AD treatment. | | 7月26日（金）8:50～9:10 第10会場（万代島ビル 6F 会議室）
2WD10bm1-2
High-fat diet exacerbates neuropathology in AppNL-F/NL-F mouse model of Alzheimer's disease
Guianfranco Mazzei（Mazzei Guianfranco）1，Nona Abolhassani（Abolhassani Nona）1，Ryohei Ikegami（Ikegami Ryohei）1，Naoki Haruyama（Haruyama Naoki）1，Takashi Saido（Saido Takashi）2，Takaomi C. Saido（Saido Takaomi C.）2，Yusaku Nakabeppu（Nakabeppu Yusaku）1
1Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
2Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama, Japan
Alzheimer's disease (AD), which accounts for the majority of dementia in the elderly population, is characterized by the accumulation of amyloid-β (Aβ) and neurofibrillary tangles in the brain. While still unclear, several factors involving lifestyle are often related to its etiology. In humans, insulin resistance, which is a major symptom of type-2 diabetes mellitus (T2DM), is a known risk factor for developing AD and recent evidence shows a shared pathophysiology in both diseases which include amyloidogenesis and cognitive decline. To understand how T2DM or related conditions contribute to AD pathogenesis, it is essential to establish good physiological models which faithfully reproduce the disease conditions. For this, we used a knock-in mouse model of AD, AppNL-F/NL-F carrying a humanized Aβ sequence together with 2 pathogenic mutations in the mouse App gene. AppNL-F/NL-F mice develop Aβ plaques from 12 months of age, a mild cognitive decline at 18 months of age, and have the advantage of avoiding the artificial influence of transgenes, which disrupt endogenous genes or are overexpressed.
In the present study, 6-months-old AppNL-F/NL-F and wild-type control (Appwt/wt) mice were fed with a regular low-fat diet (LFD) or high-fat diet (HFD) for 12 months, then we compared the effects on cognitive function, metabolic parameters, and hippocampal gene expression profile between each group. HFD successfully increased body weight mass and impaired glucose tolerance levels in both genotypes at 18 months of age. However, behavioral analysis by Morris water maze showed an impaired cognitive function only AppNL-F/NL-F mice fed with HFD. Gene expression profiling by microarray analyses revealed synergistic increases of Cd68, an activated microglial marker, in AppNL-F/NL-F mice depending on the diet and genotype. Pathway analysis showed that three genes (Eln, Lilrb4, and Cd68), whose expression was upregulated by both HFD and AppNL-F knock-in mutations, are involved in inflammatory response and hematological system development. We are currently carrying out histological analysis to elucidate the effect of HFD in AD-like pathology measuring Aβ, phosphorylated Tau, GFAP, and CD68. In conclusion, long-term exposure to HFD induced persistent impaired glucose tolerance along with cognitive deficit and microglial activation in aged AppNL-F/NL-F mouse model of AD, and thus likely to exacerbate AD-like pathology. | | 7月26日（金）9:10～9:30 第10会場（万代島ビル 6F 会議室）
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T 型 Ca2+ チャネル活性化薬 SAK3 による Aβ 凝集抑制と認知機能改善作用
Hisanao Izumi（泉 久尚），Yasuharu Shinoda（篠田 康晴），Keita Sato（佐藤 恵太），Kohji Fukunaga（福永 浩司）
東北大院薬薬理学
[Background and Objectives] Alzheimer's disease (AD) is a progressive neurodegenerative and the most common disease of elderly dementia in the world. Acetylcholinesterase inhibitors such as donepezil and rivastigmine are the most useful drug for AD, but they are only used as symptomatic treatment and not disease-modifying drugs. Recently, we developed an disease-modifying drug, SAK3 which inhibits amyloid beta aggregation (Izumi et al., 2018). We here addressed the mechanism of amyloid beta accumulation using AppNL-F knock-in mice developed by Saito and Saido et al (Saito et al., 2014).
[Methods] Using AppNL-F knock-in mice, (i) Aβ levels in the brain were quantified by Aβ ELISA kit. (ii) Aβ depositions were assessed by staining with 6E10 and Thioflavin-S. (iii) Microarray and RT-PCR analyses were conducted to elucidate the changes in gene expression.
[Results] A&beta deposition were mainly observed in the cortex in 12-month-old AppNL-F knock-in mice. Whole RNA analysis revealed that mRNA levels of ADAM10, BACE1 and neprilysin involved in production and clearance of Aβ are not changed. Interestingly, mRNA levels of SGK1 were decreased in AppNL-F knock-in mice. We succeeded to develop a new drug candidate, SAK3 which inhibits Aβ deposition in AppNL-F knock-in mice.
Reference
Izumi H, Shinoda Y, Saito T, Saido TC, Sato K, Yabuki Y, Matsumoto Y, Kanemitsu Y, Tomioka Y, Abolhassani N, Nakabeppu Y, Fukunaga K. (2018) The Disease-modifying Drug Candidate, SAK3 Improves Cognitive Impairment and Inhibits Amyloid beta Deposition in App Knock-in Mice. Neuroscience. 377:87-97.
Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC. (2014) Single App knock-in mouse models of Alzheimer's disease. Nat Neurosci. 17:661-663 | | | |
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