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研究グループは、リファンピシンの経鼻投与が前頭側頭型認知症(FTD)や筋萎縮性側索硬化症(ALS)にも有効であるとモデルマウスを用いた研究で明らかにしました。本研究結果は、リファンピシンが神経変性疾患に広く有効な薬となる可能性を示しています。FTDやALSはいまだ有効な治療法のない神経変性疾患です。原因として最も多いのがC9orf72遺伝子の非翻訳領域に存在するヘキサヌクレオチド(GGGGCC)リピートが異常伸長(HRE)する変異です。これにより生み出された異常なRNAやタンパク質が凝集し、神経系に蓄積することで神経変性が起こると考えられています。今回、本研究グループは、HREを有するC9orf72遺伝子発現モデルマウスにリファンピシンを1カ月間経鼻投与し、マウスの認知機能を観察しました。その結果、リファンピシンを投与することでHREに起因する神経病理が抑制され、マウスの認知機能が改善することが明らかになりました。, The non-coding GGGGCC hexanucleotide repeat expansion (HRE) in C9orf72 gene is a dominant cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This intronic mutation elicits the formation of nuclear and cytoplasmic inclusions containing RNA, RNA-binding proteins, and HRE-derived dipeptide repeat proteins (DPRs), leading to neurodegeneration via the gain-of-toxic function or loss-of-function of relevant proteins. Using C9-500 mice harboring ~500 repeats of the GGGGCC sequence in human C9orf72 gene, we investigated the effects of rifampicin against HRE-related pathological phenotypes. Rifampicin was administered intranasally to 4.5- to 5-month-old mice for 1 month, and their cognitive function and neuropathology were assessed by the Morris water maze test and immunohistochemical staining. Rifampicin treatment reduced the formation of RNA foci and cytoplasmic inclusions containing DPRs or phosphorylated TDP-43, and furthermore, the levels of phosphorylated double-strand RNA-dependent protein kinase (PKR) that regulates repeat-associated non-ATG (RAN) translation. Synapse loss in the hippocampus and neuronal loss and microglial activation in the prefrontal and motor cortices were also attenuated, and mouse memory was significantly improved. Our findings suggest a therapeutic potential of nasal rifampicin in the prevention of C9orf72-linked neurodegenerative disorders.

Recent evidence suggests that the formation of soluble amyloid β (Aβ) aggregates with high toxicity, such as oligomers and protofibrils, is a key event that causes Alzheimer’s disease (AD). However, understanding the pathophysiological role of such soluble Aβ aggregates in the brain in vivo could be difficult due to the lack of a clinically available method to detect, visualize, and quantify soluble Aβ aggregates in the brain. We had synthesized a novel fluorinated curcumin derivative with a fixed keto form, named as Shiga-Y51, which exhibited high selectivity to Aβ oligomers in vitro. In this study, we investigated the in vivo detection of Aβ oligomers by fluorine-19 (19F) magnetic resonance imaging (MRI) using Shiga-Y51 in an APP/PS1 double transgenic mouse model of AD. Significantly high levels of 19F signals were detected in the upper forebrain region of APP/PS1 mice compared with wild-type mice. Moreover, the highest levels of Aβ oligomers were detected in the upper forebrain region of APP/PS1 mice in enzyme-linked immunosorbent assay. These findings suggested that 19F-MRI using Shiga-Y51 detected Aβ oligomers in the in vivo brain. Therefore, 19F-MRI using Shiga-Y51 with a 7 T MR scanner could be a powerful tool for imaging Aβ oligomers in the brain.