一般口演
アルツハイマー病と認知症 2
Alzheimer's Disease and Dementia 2
座長：斉藤 貴志（名古屋市立大学医学研究科） |
|---|
| 2022年7月3日 11:00～11:15 沖縄コンベンションセンター 会議場B2 第5会場
4O05a1-01
アルツハイマー病マウスの記憶機能障害に対するP2Y1受容体ノックアウトの効果
The effect and mechanism of P2Y1 receptor knockout on memory dysfunction in Alzheimer's disease mice
*羅 珊(1)、白井 隆貴(1)、玉田 あみ(1)、齋川 雄一(1)、久恒 辰博(1)
1. 東京大学
*SHAN LUO(1), Takaki Shirai(1), Ami Tamada(1), Yuichi Saikawa(1), Tatsuhiro Hisatsune(1)
1. The University of Tokyo
Keyword: P2Y1 receptor, Alzheimer’s disease, astrocytic hyperactivity, platelet aggregation
P2Y1R, a purinoreceptor, mainly expressed in platelets, endothelial cells, epithelial cells, and astrocytes, has been shown to impair the cognitive function of Alzheimer's mice, but the underlying pathways have remained undefined. In this study, we used P2Y1 knockout mice to verify the function of P2Y1 in high-fat-diet and normal APP/PS1 Alzheimer's disease mice. Morris water maze and contextual fear conditioning test were used to test spatial memory and fear memory. Immunofluorescence analysis revealed amyloid plaques, over-activated astrocytes, and microglia, as well as fibrin aggregation on blood vessels. ELISA was used to measure the concentrations of Aβ42, and CXCL12 (inflammatory chemokines) in AD mice. According to our study, the spatial cognitive capacity and fear memory of P2Y1KO AD mice was improved. Our findings also imply that memory function in P2Y1KO AD mice can be maintained in two ways. Firstly, knocking out P2Y1R can normalize astrocytic and microglial hyperactivity which indicates that the P2Y1R is involved in brain neuroinflammation of Alzheimer's disease. We speculate that this change may reduce the production of inflammatory factors that prevent nerve cell death and maintain memory and cognitive function. Second, the content of CXCL12 in serum and Aβ peptides in the brain of APP/P2Y1KO mice were both reduced. The role of the P2Y1 receptor in platelet aggregation may help to explain how this happens. All in all, our findings show that P2Y1R is linked to Alzheimer's disease and can be considered a therapeutic target. | | 2022年7月3日 11:15～11:30 沖縄コンベンションセンター 会議場B2 第5会場
4O05a1-02
rTg4510認知症モデル動物脳における炎症性アストロサイト病態の画像解析
In vivo assessment of progressive astrogliosis in the pathophysiological cascade of rTg4510 tauopathy animal brains
*下條 雅文(1)、南久松 丈晴(1)、高橋 真奈美(1)、田桑 弘之(1)、松下 有美(1)、矢内 凛(1)、湊原 圭一郎(1)、小野 麻衣子(1)、高堂 裕平(1)、張 明栄(2)、佐原 成彦(1)、樋口 真人(1)
1. 量子科学技術研究開発機構 脳機能イメージング研究部、2. 量子科学技術研究開発機構 先進核医学基盤研究部
*MASAFUMI SHIMOJO(1), Takeharu Minamihisamatsu(1), Manami Takahashi(1), Hiroyuki Takuwa(1), Yumi Matsushita(1), Rin Yanai(1), Keiichiro Minatohara(1), Maiko Ono(1), Yuhei Takado(1), Ming-Rong Zhang(2), Naruhiko Sahara(1), Makoto Higuchi(1)
1. Dept. of Func Brain Imaging, QST, Chiba, Japan, 2. Dept. of Ad Nuc Med Sci, QST, Chiba, Japan
Keyword: Tau, Inflammation, Astrocyte, imaging
Progressive inflammatory gliosis associated with neuronal deposition of hyperphosphorylated tau is currently hypothesized as a key component in the early stage of pathological cascade in neurodegenerative tauopathies including Alzheimer’s disease. Cumulative evidence indicates that astrocyte activates in response to pathological tau accumulation and transforms its gene expression and cellular composition from a physiological state to a reactive state. However, it is still not fully clarified when and how this astrocytic transition occurs during the disease progress. To address this fundamental question, we investigated the time-course change of astrocytic pathophysiology and its intracellular compositions in the forebrain of rTg4510 mouse model of tauopathy, which typically develops tau depositions and brain atrophy at 5-6 months of age. In the conventional biochemical and immunohistochemical assessment of postmortem brain tissues, we first demonstrate that alteration of several astrocytic constituents represented by GFAP has been already initiated without robust pathological tau deposition and brain atrophy in the neocortex of rTg4510 mice at 2-3 months of age. We also show that astrocytic spontaneous Ca2+ oscillation in rTg4510 brain subtly changes at this stage by a two-photon microscope, suggesting the early event of pathological tau accumulation in neurons may be enough to elicit the reactivity of astrocyte. Furthermore, utilizing the reporter imaging technique for positron emission tomography (PET) that we currently established, we examine whether longitudinal in vivo assessment of the macroscopic distribution and cellular state transition of astrocytes can be achieved. Our findings indicate that tau-induced astrogliosis may be a critical early trigger for further inflammatory response and neurodegeneration, and further investigation to dissect more detailed biological consequences underlying inflammation and tau pathology is still in progress. | | 2022年7月3日 11:30～11:45 沖縄コンベンションセンター 会議場B2 第5会場
4O05a1-03
アルツハイマー病態におけるHMGB1シグナルによるKu70リン酸化はDNA損傷修復を阻害する
HMGB1 signaling phosphorylates Ku70 and impairs DNA damage repair in Alzheimer’s disease pathology
*田中 ひかり(1)、近藤 和(1)、藤田 慶大(1)、本間 秀典(1)、田川 一彦(1)、Xiaocen Jin(1)、Meihua Jin(1)、吉岡 優希(1)、高山 すみれ(1)、岡澤 均(1,2)
1. 東京医科歯科大学 難治疾患研究所 神経病理学分野、2. 脳統合機能研究センター
*Hikari Tanaka(1), Kanoh Kondo(1), Kyota Fujita(1), Hidenori Homma(1), Kazuhiko Tagawa(1), Xiaocen Jin(1), Meihua Jin(1), Yuki Yoshioka(1), Sumire Takayama(1), Hitoshi Okazawa(1,2)
1. Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University , 2. Center for Brain Integration Research
Keyword: Alzheimer’s disease, DNA damage repair, Senescence, TRIAD necrosis
The accumulating evidences indicate impairment of DNA damage repair as a common pathological domain across neurodegenerative diseases. DNA damage is increased in Alzheimer’s disease (AD), while the underlying mechanisms are unknown. Here, we employ comprehensive phosphoproteome analysis, and identify abnormal phosphorylation of 70 kDa subunit of Ku antigen (Ku70) at Ser77/78, which prevents Ku70-DNA interaction, in human AD postmortem brains. The abnormal phosphorylation inhibits accumulation of Ku70 to the foci of DNA double strand break (DSB), impairs DNA damage repair and eventually causes transcriptional repression-induced atypical cell death (TRIAD). Extracellular high mobility group box 1 (HMGB1) protein, which is released from necrotic or hyper-activated neurons in AD, binds to toll-like receptor 4 (TLR4) of neighboring neurons, and activates protein kinase C alpha (PKCα) that executes Ku70 phosphorylation at Ser77/78. Administration of human monoclonal anti-HMGB1 antibody to post-symptomatic AD model mice decreases neuronal DSBs, suppresses secondary TRIAD necrosis of neurons, prevents escalation of neurodegeneration, and ameliorates cognitive symptoms.
Furthermore, TRIAD is found to share common features with senescence. Both biological processes share DNA damage, SASP/DAMP secretion (especially secretion of HMGB1), transcriptional change, and apoptosis resistance with TRIAD necrosis. Biomarker-based analyses in this study further supported the identity of TRIAD and senescence, indicating that TRIAD is the end stage of senescence phenotype of neurons in neurodegeneration and aging brains.
These results discover the HMGB1-Ku70 axis that accounts for the increase of neuronal DNA damage and secondary enhancement of TRIAD, the cell death phenotype of senescence, in AD. | | 2022年7月3日 11:45～12:00 沖縄コンベンションセンター 会議場B2 第5会場
4O05a1-04
アルツハイマー病に関連したCD33選択的スプライシングの制御因子
Identification of the proteins that regulate the Alzheimer's disease-associated splicing of CD33
*紀 嘉浩(1)、小室 璃歩(1)、本多 由佳(1)、柳津 茂慧(1)、佐藤 準一(1)
1. 明治薬科大学
*Yoshihiro Kino(1), Riho Komuro(1), Yuka Honda(1), Motoaki Yanaizu(1), Jun-ichi Satoh(1)
1. Meiji Pharmaceutical University
Keyword: Alzheimer's disease, CD33, splicing, microglia
Genetic variation of CD33 has been implicated as a risk factor of Alzheimer’s disease (AD), a leading cause of dementia in elderly. CD33 is a transmembrane immune receptor highly expressed on microglia and binds to sialic acids that are found in glycoproteins and glycolipids through its extracellular domain. A polymorphism on exon 2 of CD33, rs12459419, has been implicated in the alternative splicing of this exon as well as the risk of AD. Skipping of exon 2 results in the production of the shorter CD33 isoform lacking extracellular ligand-binding domain, leading to diminution of suppressive signaling on microglial activity exerted by CD33. The minor allele of rs12459419 is associated with preferential exon 2 skipping and is protective against the risk of AD. Thus, it is likely that regulatory factors of the splicing of exon 2 may alter the disease-associated activity of CD33. Here, we established a minigene assay of human CD33, which reflected the known effect of the rs12459419 polymorphism. Using a panel of RNA-binding proteins, we found that hnRNPA1 promotes exon 2 skipping of CD33. Although knockdown of hnRNPA1 alone did not reduce exon 2 skipping, simultaneous knockdown of hnRNPA1 together with hnRNPA2B1 and hnRNPA3 promoted exon 2 inclusion, suggesting that hnRNPA family proteins redundantly regulate the splicing of CD33. Consistently, overexpression of either hnRNPA2B1 or hnRNPA3 induced exon 2 skipping like hnRNPA1. Similar redundant regulation of alternative splicing by hnRNPA family proteins was observed in the exon 2 splicing of a murine Cd33 minigene. Meanwhile, mouse Cd33 showed a unique splicing pattern that was not observed in the human counterpart. Collectively, our results established a novel regulatory relationship between CD33 and hnRNPA proteins. | |
|
|
