一般口演
アルツハイマー病と認知症 1
Alzheimer's Disease and Dementia 1
座長：梅田 知宙（大阪市立大学 大学院医学研究科） |
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| 2022年7月2日 9:00～9:15 沖縄コンベンションセンター 会議場B5～7 第4会場
3O04m1-01
アルツハイマー病モデルマウスにおいて、HDAC3阻害はマイクログリアから分泌されるIGFBP6を介して変性軸索を正常化させ、記憶回復作用を示す
HDAC3 inhibition ameliorates dystrophic axons and memory function via secretion of IGFBP6 from microglia in a transgenic mouse model of Alzheimer’s disease
*久保山 友晴(1)、岡本 陽里(1)、東田 千尋(2)
1. 第一薬科大学薬学部、2. 富山大学和漢医薬学総合研究所
*Tomoharu Kuboyama(1), Hikari Okamoto(1), Chihiro Tohda(2)
1. Lab of Pharmacognosy, Daiichi Univ of Pharmacy, Fukuoka, Japan, 2. Sec of Neuromedical Science, Inst of Natural Medicine, Univ of Toyama, Toyama, Japan
Keyword: Alzheimer's disease, microglia, HDAC3, axon
Amyloid β (Aβ) skews microglia to M1 phenotype and induces inflammation and neurodegeneration. On the other hand, another type of microglia, M2, shows anti-inflammatory and neurotrophic effects. We previously clarified that HDAC3 inhibition induced predominance of M2 microglia and axonal growth, and recovered locomotor function in spinal cord injured mice. Therefore, this study aimed to clarify that HDAC3 inhibition skewed to M2 microglia and restored memory function in Alzheimer’s disease model mice. In cultured microglia, a treatment with an HDAC3 inhibitor, RGFP966, skewed to M2 microglia when treated 24 h after Aβ addition. Conditioned medium collected from RGFP966-treated microglia recovered Aβ-induced collapse of axonal growth cones. RGFP966 was intraperitoneally administered to 5XFAD mice, a transgenic model of Alzheimer’s disease. RGFP966 decreased degenerated axons overlapping with Aβ plaques and improved novel object recognition memory. When microglia in the brain of 5XFAD mice were eliminated by intracerebroventricular administration of clophosome, the effects of RGFP966 were diminished. IGFBP6 was identified from the microglial conditioned medium after RGFP966 treatment. Treatment with IGFBP6 recovered Aβ-induced collapse of axonal growth cones in cultured neurons. A functional blocking antibody for IGFBP6 inhibited the effect of the microglial conditioned medium after RGFP966 treatment on recovery from Aβ-induced collapse of axonal growth cones. The antibody also inhibited the effect of RGFP966 on memory recovery in 5XFAD mice. These results suggest that HDAC3 inhibition skewed to M2 microglia, promoted IGFBP6 secretion from microglia, recovered axonal degeneration, and ameliorated memory deficit in 5XFAD mice. | | 2022年7月2日 9:15～9:30 沖縄コンベンションセンター 会議場B5～7 第4会場
3O04m1-02
リファンピシン＋レスベラトロール合剤の経鼻投与によるオリゴマー除去と認知症予防
Oligomer-Targeting Prevention of Neurodegenerative Dementia by Intranasal Rifampicin and Resveratrol Combination
*梅田 知宙(1)、酒井 亜由美(1)、重森 慶子(1)、横田 あゆみ(1)、熊谷 徹(2)、富山 貴美(1,2)
1. 大阪市立大学 大学院医学研究科、2. 株式会社メディラボRFP
*Tomohiro Umeda(1), Ayumi Sakai(1), Keiko Shigemori(1), Ayumi Yokota(1), Toru Kumagai(2), Takami Tomiyama(1,2)
1. Grad Sch Med, Osaka City Univ, Osaka, Japan, 2. MedilaboRFP
Keyword: Anti-dementia drug, Rifampicin, Resveratrol, Amyloidgenic protein oligomers
Amyloidogenic protein oligomers are thought to play an important role in the pathogenesis of neurodegenerative dementia, including Alzheimer’s disease, frontotemporal dementia, and dementia with Lewy bodies. Previously we demonstrated that oral or intranasal rifampicin improved the cognition of APP-, tau-, and α-synuclein-transgenic mice by reducing the amount of Aβ, tau, and α-synuclein oligomers in the brain. In the present study, to explore more effective and safer medications for dementia, we tested the drug combination of rifampicin and resveratrol, which is a multifunctional natural polyphenol with the potential to antagonize the adverse effects of rifampicin. The mixture was intranasally administered to APP-, tau-, and α-synuclein-transgenic mice, and their memory and oligomer-related pathologies were evaluated. Compared with rifampicin and resveratrol alone, the combinatorial medicine significantly improved mouse cognition, reduced amyloid oligomer accumulation, and recovered synaptophysin levels in the hippocampus. The plasma levels of liver enzymes, which reflect hepatic injury and normally increase by rifampicin treatment, remained normal by the combination treatment. Notably, resveratrol alone and the combinatorial medicine, but not rifampicin alone, enhanced the levels of brain-derived neurotrophic factor (BDNF) and its precursor, pro-BDNF, in the hippocampus. Furthermore, the combination showed a synergistic effect in ameliorating mouse cognition. These results show the advantages of this combinatorial medicine with regards to safety and effectiveness over single-drug rifampicin. Our findings may provide a feasible means for the prevention of neurodegenerative dementia that targets toxic oligomers. | | 2022年7月2日 9:30～9:45 沖縄コンベンションセンター 会議場B5～7 第4会場
3O04m1-03
脈絡叢分泌性miRNAの成体海馬ニューロン新生における役割
miRNAs secreted from choroid plexus plays a critical role for the maintenance of neurogenesis in the aged brain
*堅田 明子(1)、榊 佑介(1)、中島 欽一(1)
1. 九州大学大学院
*Sayako Katada(1), Yusuke Sakaki(1), Kinichi Nakashima(1)
1. Kyushu University
Keyword: Cerebrospinal fluid, miRNA, Aging, Exosomes
Although neural stem cells (NSCs) produce new neurons even in adulthood, neurogenesis decreases with age and its underlying mechanisms remain largely unknown. Several studies have reported that cerebrospinal fluid (CSF), which is primarily produced by the choroid plexus (ChP) in ventricles, serves as a niche for NSCs. ChP is a highly vascularized epithelial tissue constituting blood-CSF barrier and secretes variety of signaling molecules into CSF. We have previously performed RNA-seq analyses of the ChP in the lateral ventricle (LVChP) of young (3 months) and aged (21 months) mice, and identified hundreds of differentially expressed genes (DEGs), however, expression of renown growth factors for NSCs did not dramatically changed between young and aged stages. Gene set enrichment- and pathway-analysis of DEGs revealed that genes in microRNA (miRNA) biogenesis and exosomal secretion pathways are down-regulated in aged ChP. Since miRNAs are loaded into exosomes for secretion and directly regulate gene expression in trans, we performed small RNA-seq analysis to identify miRNAs expressed in the LVChP. In accordance with the above results, miRNA expression was generally decreased in the aged LVChP, including 66 of significantly downregulated miRNAs. On the other hands, expression of 5 miRNAs was dramatically increased in the aged mice. We then directly overexpressed these identified miRNAs in NSCs and found that some enhanced NSC proliferation. We next evaluate functions of these miRNAs in vivo, by using AAV-5, which is known to preferentially infect ChP epithelial cells when injected into the lateral ventricle. When we knocked-down these miRNAs in the LVChP, decrease in the amount of target miRNAs in CSF was consistently observed. We found that some of these miRNAs indeed regulate NSCs’ behavior, affecting neurogenesis in the mouse brain. Altogether, our findings suggest that the expression change of miRNAs in ChP is implicated in the regulation of NSCs during brain aging, and ChP-derived miRNAs can be potential therapeutic targets for age-associated brain disorders such as dementia and Alzheimer’s disease. | | 2022年7月2日 9:45～10:00 沖縄コンベンションセンター 会議場B5～7 第4会場
3O04m1-04
アルツハイマー病の発病過程においてMTH1とOGG1はミクログリオーシスを抑制するが、MUTYHはミクログリアの活性化と神経新生の障害に能動的に寄与する
MTH1 and OGG1 suppress microgliosis, while MUTYH actively contributes to microglial activation and impaired neurogenesis in the pathogenesis of Alzheimer’s disease
*中別府 雄作(1)、水野 裕理(1,2)
1. 九州大学生体防御医学研究所、2. 九州大学大学院医学系学府
*Yusaku Nakabeppu(1), Yuri Mizuno(1,2)
1. Med Inst Bioreg, Kyushu Univ, Fukuoka, Japan, 2. Grad Sch Med, Kyushu Univ, Fukuoka, Japan
Keyword: 8-oxoguanine, MTH1, OGG1, MUTYH
Oxidative stress is a major risk factor for Alzheimer’s disease (AD). Among various oxidized molecules, the marked accumulation of an oxidized form of guanine, 8-oxo-7,8-dihydroguanine (8-oxoG), is observed in the AD brain. In mammalian cells, several enzymes play essential roles in minimizing the 8-oxoG accumulation in DNA. 8-oxo-2´-deoxyguanosine triphosphatase (8-oxo-dGTPase; MTH1) and 8-oxoG DNA glycosylase (OGG1) minimize the 8-oxoG accumulation in DNA, and their expression is decreased in the AD brain. MUTYH with adenine DNA glycosylase activity excises adenine inserted opposite 8-oxoG in DNA, and its expression is increased in the AD brain. We evaluated the roles of MTH1, OGG1 and MUTYH during the pathogenesis of AD using AppNL-G-F/NL-G-F knock-in mice which produce humanized toxic amyloid-β without the overexpression of APP protein. AppNL-G-F/NL-G-F mice with MTH1 and/or OGG1 deficiency exhibited reduced anxiety-related behavior, but their cognitive and locomotive functions were unchanged. MTH1 and/or OGG1 deficiency accelerated the 8-oxoG accumulation and microgliosis in the amygdala and cortex. These data indicate that MTH1 and OGG1 are essential for minimizing oxidative DNA damage in the AppNL-G-F/NL-G-F brain, especially in cortex and amygdala, thus suppressing microgliosis. We further introduced MUTYH deficiency into AppNL-G-F/NL-G-F knock-in mice, and found that MUTYH deficiency improved memory impairment in AppNL-G-F/NL-G-F mice, accompanied by reduced microgliosis. Gene expression profiling strongly suggested that MUTYH is involved in the microglial response pathways under AD pathology and contributes to induction of disease-associated microglia. We also found that MUTYH deficiency ameliorates impaired neurogenesis in the hippocampus, thus improving memory impairment. In conclusion, we propose that MTH1 and OGG1 suppress microgliosis but MUTYH actively contributes to memory impairment by inducing microgliosis with poor neurogenesis in the preclinical AD phase and that MUTYH is a novel therapeutic target for AD, as its deficiency is highly beneficial for ameliorating AD pathogenesis. | |
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