一般口演（Oral）

Oral Alzheimer's disease-2 一般口演アルツハイマー病-2

7月27日（土）15:20～15:35　第8会場（朱鷺メッセ　3F　303+304） 3O-08a2-1 Altered gene expression profiles in Alzheimer´s disease model mice caused by deficiency in three genes counteracting the buildup of 8–oxoguanine in DNA Nona Abolhassani（Abolhassani Nona）¹，Yuri Mizuno（Mizuno Yuri）¹，Guianfranco Mazzei（Mazzei Guianfranco）¹，Takashi Saito（Saito Takashi）²，Takaomi C. Saido（Saido Takaomi C.）²，Yusaku Nakabeppu（Nakabeppu Yusaku）¹ ¹Medical Institute of Bioregulation, Kyushu University ²Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama, Japan. Alzheimer´s disease (AD) is the most common form of dementia, characterized by accumulation of amyloid Β and neurofibrillary tangles. Oxidative stress and inflammation are considered to play important roles in AD pathogenesis. Among various oxidized bases, 8–oxoguanine (8–oxoG) is known to be highly accumulated in postmortem AD brain. The buildup of 8–oxoG in DNA is caused by direct oxidation of guanine in DNA or through incorporation of 8–oxoG from nucleotide pools. In mammals including humans, three enzymes, MTH1 (8–oxo–dGTPase), OGG1 (8–oxoG DNA glycosylase) and MUTYH (adenine DNA glycosylase), have been shown to play important roles in counteracting the buildup of 8–oxoG in DNA. In this study, we used a knock–in mouse model of AD, App^{NL-G-F/NL-G-F} carrying humanized pathogenic mutations in mouse App gene. By mating App^{NL-G-F/NL-G-F} with Mth1^+/-, Ogg1^+/- or Mutyh^+/- mice, we established 5 different mouse lines, App^{NL-G-F/NL-G-F}, App^{NL-G-F/NL-G-F}·Mth1^-/-, App^{NL-G-F/NL-G-F}·Ogg1^-/-, App^{NL-G-F/NL-G-F}·Mutyh^-/-, and wild-type control, App^+/+ mice. We obtained their expression profiles of hippocampal genes by microarray analysis at 6 months of age, and compared expression levels of genes encoding specific markers for 4 major types of brain cells. We found significantly increased expression of Cd68, an activated microglial marker, in 4 mouse lines with App^{NL-G-F/NL-G-F} genotype compared to the wild-type control, while only MUTYH deficiency significantly decreased the expression level of Cd68 compared to App^{NL-G-F/NL-G-F}. We also found that expression levels of neuronal markers do not decreased at this age in the 4 mouse lines with App^{NL-G-F/NL-G-F}genotype. Among the top 27 genes whose expression levels were significantly altered by App^{NL-G-F/NL-G-F}genotype, MUTYH deficiency significantly reversed increased expression levels of Cst7, Ccl6 and Lyz2 which are known to be involved in immunoregulatory processes, thus suggesting suppression of neuroinflammation. On the other hand, OGG1 deficiency synergistically increased expression levels of Clec7a, Cd180 and Itgax, which are also involved in immunoregulatory processes, suggesting enhanced neuroinflammation. Besides, expression level of Trem2, which is known to be associated with the risk of AD, was synergistically increased by MTH1 deficiency and App^{NL-G-F/NL-G-F} genotype. In conclusion our results indicate that deficiency in OGG1, MUTYH or MTH1 differentially modify the AD pathogenesis in App^{NL-G-F/NL-G-F} mice.		7月27日（土）15:35～15:50　第8会場（朱鷺メッセ　3F　303+304） 3O-08a2-2 発達障害原因遺伝子PQBP1はアルツハイマー病態を制御する Hikari Tanaka（田中ひかり）¹，Kanoh Kondo（近藤和）¹，Xigui Chen（Chen Xigui）¹，Hidenori Homma（本間秀典）¹，Kazuhiko Tagawa（田川一彦）¹，Aurelien Kerever（Kerever Aurelien）²，Shigeki Aoki（青木茂樹）²，Takashi Saito（齊藤貴志）³，Takaomi Saido（西道隆臣）³，Shin-ichi Muramatsu（村松慎一）⁴ ¹東医歯大院難治研神経病理 ²順天堂大学放射線医学教室 ³理研CBS 神経老化制御 ⁴自治医大医神経内科 Alzheimer's disease (AD) is the most common form of dementia, involving memory loss and a reduction in cognitive abilities. Early-phase pathologies of AD are attracting much attention after clinical trials of drugs designed to remove beta-amyloid (Aβ) aggregates failed to recover memory and cognitive function in symptomatic AD patients. Here, we show that phosphorylation of serine/arginine repetitive matrix 2 (SRRM2) at Ser1068, which is observed in the brains of early phase AD mouse models and postmortem end-stage AD patients, prevents its nuclear translocation by inhibiting interaction with T-complex protein subunit α. SRRM2 deficiency in neurons destabilized polyglutamine binding protein 1 (PQBP1), a causative gene for intellectual disability (ID), greatly affecting the splicing patterns of synapse-related genes, as demonstrated in a newly generated PQBP1-conditional knockout model. PQBP1 and SRRM2 were downregulated in cortical neurons of human AD patients and mouse AD models, and the AAV-PQBP1 vector recovered RNA splicing, the synapse phenotype, and the cognitive decline in the two mouse models. Finally, the kinases responsible for the phosphorylation of SRRM2 at Ser1068 were identified as ERK1/2 (MAPK3/1). These results collectively reveal a new aspect of AD pathology in which a phosphorylation signal affecting RNA splicing and synapse integrity precedes the formation of extracellular Aβ aggregates A and may progress in parallel with tau phosphorylation.

7月27日（土）15:50～16:05　第8会場（朱鷺メッセ　3F　303+304） 3O-08a2-3 高精度視線検出技術による注視点データ解析に基づいた認知症迅速スクリーニング法の確立 Shuko Takeda（武田朱公）¹，Akane Oyama（大山茜）²，Yuki Ito（伊藤祐規）¹，Tsuneo Nakajima（中嶋恒男）²，Yoichi Takami（鷹見洋一）²，Yasushi Takeya（竹屋泰）²，Koichi Yamamoto（山本浩一）²，Ken Sugimoto（杉本研）²，Hiromi Rakugi（樂木宏実）²，Ryuichi Morishita（森下竜一）¹ ¹大阪大学大学院医学系研究科　臨床遺伝子治療学 ²大阪大学大学院医学系研究科　老年・総合内科学 A rapid increase in the number of patients with dementia, including the related economic burden, has emerged as a global health challenge. Accumulating evidence suggests that early diagnosis and timely intervention can delay or prevent cognitive decline. The diagnosis of dementia is commonly performed using neuropsychological tests, such as the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog), administered by physicians or trained examiners. While these traditional neuropsychological tests are valid and reliable, they are neither simple nor sufficiently short as routine screening tools for dementia. Here, we developed a brief and practical cognitive assessment utilizing a high-performance eye-tracking technology. The subject views a series of short (178 s) task movies displayed on a monitor while their gaze points are recorded by the eye-tracking device, and the cognitive scores are determined from the gaze plots data. The cognitive scores were measured by both an eye tracking-based assessment and traditional neuropsychological tests in 85 participants in total, including 28 cognitively healthy controls (HC), 31 patients with mild cognitive impairment (MCI), and 26 patients with dementia. The eye tracking-based cognitive scores correlated well with the scores from the MMSE and other neuropsychological tests, and they showed a good diagnostic performance in detecting cognitive impairment in patients with MCI and dementia. Rapid cognitive assessment using eye-tracking technology can reduce psychological stress, which subjects may experience during long cognitive tests, and it can enable quantitative scoring and the sensitive detection of cognitive impairment.		7月27日（土）16:05～16:20　第8会場（朱鷺メッセ　3F　303+304） 3O-08a2-4 Bulbous axonal sprouting is a reversible cause of action potential conduction failure in Alzheimer Disease Peng Yuan（Yuan Peng）^1,3，Mengyang Zhang（Zhang Mengyang）^1,2，Lei Tong（Tong Lei）^1,2，Thomas Morse（Morse Thomas）²，Robert McDougal（McDougal Robert）²，Diane Chan（Chan Diane）¹，Fuyi Chen（Chen Fuyi）¹，Jaime Grutzendler（Grutzendler Jaime）^1,2 ¹Department of Neurology, Yale School of Medicine ²Department of Neuroscience, Yale University ³Department of Biology, Stanford University In Alzheimer's disease (AD), amyloid deposits are surrounded by hundreds of axons with prominent swellings, classically termed dystrophic neurites. These structures have been recognized histologically for more than a century, as they are prevalent in AD brain and are associated with cognitive deficits. However, the mechanisms of formation and biophysical impact on neuronal function of these axonal spheroids (AS) remain unknown. We show by in vivo imaging that AS are not retraction bulbs associated with ongoing axonal degeneration. Instead, AS are persistent structures that markedly disrupt action potential conduction; and correlate well with the degree of cognitive decline in humans. We provide a biophysical mechanism that AS disrupt axonal conduction by acting as electric current sinks. Furthermore, we identified that AS develop through a previously unrecognized active process of focal axonal sprouting with formation of end-bulbs, driven by aberrant accumulation of structurally and functionally abnormal lysosomes. Neuronal inhibition of ArpC3 or GAP43 to prevent sprouting, or overexpression of lysosomal protease Cathepsin-D, markedly reduced AS numbers and size, respectively. Thus, reversal of AS pathology may restore neuronal network function in AD, potentially constituting a novel therapeutic target, independent of amyloid removal. Our work propels axonal spheroids to the forefront of potentially reversible and targetable factors in AD pathogenesis. Furthermore, the unique biology of AS opens many mechanistic questions that have important implications in the AD field.