WD7-1
Roles of cysteine residues in the microtubule-binding repeats of tau protein in its stability and toxicity
アルツハイマー病関連たんぱく質タウの微小管結合領域に存在するCysteine残基がモノマーの蓄積と毒性に果たす役割
Chiku Tomoki（知久 朋樹）1，岡 未来子1，斎藤 太郎1，浅田 明子1，飯島 浩一2,3，安藤 香奈絵1
1Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University,Tokyo, Japan
2Department of Alzheimer's Disease Research, National Center for Geriatrics and Gerontology, Aichi 474-8511, Japan
3Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan
Microtubule-associated protein tau accumulates in the brain of patients suffering from a group of neurodegenerative diseases called tauopathies. Tau assembles into various forms of aggregates and deposits in disease brains. However, the mechanisms by which tau accumulate and gain toxicity in disease brains are not fully understood. To tackle this question, we established transgenic fly lines that express mutant forms of human tau with different aggregation propensity and compare accumulation of tau protein and the degree of neurodegeneration. Among these lines, we found that alanine substitutions C291 and C322 (C291A/C322A) reduce tau toxicity dramatically. We also found that introduction of this mutation reduced tau protein levels. These sites have been known to affect tau conformation via formation of intra- and inter-molecular S-S bond, and it was previously reported that capping these sites mitigates tau toxicity via blocking dimer and oligomer formations. However, since tau dimer is detected only at low levels in the Drosophila model, C291A/C322A mutations likely affect stability and toxicity of monomeric forms of tau. Reduction in tau levels caused by the introduction of C291A/C322A mutations were also observed in mouse primary cultured neurons. Alanine substitution of either C291 or C322 was sufficient to reduce tau levels, suggesting that an intramolecular interaction between these sites play critical roles in tau stability. Further analyses of the underlying mechanisms will enhance our understanding of disease pathogenesis and may lead to novel therapy. | | WD7-2
Amyloid beta aggregation in APP knock-in mice and its inhibitor
App knock-in におけるアミロイドベータ蛋白質の凝集と阻害薬
Izumi Hisanao（泉 久尚），篠田 康晴，佐藤 恵太，福永 浩司
Dept. Pharmacol., Grad. Sch. Pharm. Sci., Tohoku Univ.
[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] Aβ 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.ReferenceIzumi 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 |
