对晚期阿尔茨海默病(AD)小鼠模型进行静脉注射伴侣素治疗,可影响淀粉样斑块负荷、反应性胶质细胞增生和AD相关基因。

IF 5.8 1区 医学 Q1 PSYCHIATRY
Ruixin Zhang, Makiko Ohshima, David Brodin, Yu Wang, Antonin Morancé, Marianne Schultzberg, Gefei Chen, Jan Johansson
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引用次数: 0

摘要

我们需要有效防治阿尔茨海默病(AD)的治疗策略。BRICHOS是一种分子伴侣结构域,可防止淀粉样蛋白纤维的形成和相关的细胞毒性。在这项研究中,我们利用静脉注射重组人(rh)Bri2 BRICHOS R221E来治疗发病七个月后的AD小鼠模型。通过神经胶质纤维酸性蛋白(GFAP)和电离钙结合适配分子 1(Iba1)免疫组化测定,AD 小鼠每周注射两次 rh Bri2 BRICHOS R221E,连续注射三个月,可减少淀粉样蛋白 β(Aβ)负担,减轻星形胶质细胞和小胶质细胞病变。对大脑皮层小胶质细胞的 RNA 测序显示,BRICHOS 治疗可使小鼠和人类中已确定的斑块诱导基因(包括集束蛋白和 GFAP)的表达正常化。Rh Bri2 BRICHOS R221E 在年龄匹配的野生型小鼠体内通过血脑屏障(BBB)的效率与在 AD 小鼠体内通过血脑屏障(BBB)的效率相同,但对类似于 AD 的病理学指标没有影响,主要影响的是影响细胞形状和运动的基因的表达。这些结果表明,rh Bri2 BRICHOS具有抗晚期AD的潜力,并强调了BRICHOS针对淀粉样蛋白诱导的病理学的能力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Intravenous chaperone treatment of late-stage Alzheimer´s disease (AD) mouse model affects amyloid plaque load, reactive gliosis and AD-related genes.

Treatment strategies that are efficient against established Alzheimer's disease (AD) are needed. BRICHOS is a molecular chaperone domain that prevents amyloid fibril formation and associated cellular toxicity. In this study, we treated an AD mouse model seven months after pathology onset, using intravenous administration of recombinant human (rh) Bri2 BRICHOS R221E. Two injections of rh Bri2 BRICHOS R221E per week for three months in AD mice reduced amyloid β (Aβ) burden, and mitigated astro- and microgliosis, as determined by glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba1) immunohistochemistry. Sequencing of RNA from cortical microglia cells showed that BRICHOS treatment normalized the expression of identified plaque-induced genes in mice and humans, including clusterin and GFAP. Rh Bri2 BRICHOS R221E passed the blood-brain barrier (BBB) in age-matched wild-type mice as efficiently as in the AD mice, but then had no effect on measures of AD-like pathology, and mainly affected the expression of genes that affect cellular shape and movement. These results indicate a potential of rh Bri2 BRICHOS against advanced AD and underscore the ability of BRICHOS to target amyloid-induced pathology.

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来源期刊
CiteScore
11.50
自引率
2.90%
发文量
484
审稿时长
23 weeks
期刊介绍: Psychiatry has suffered tremendously by the limited translational pipeline. Nobel laureate Julius Axelrod''s discovery in 1961 of monoamine reuptake by pre-synaptic neurons still forms the basis of contemporary antidepressant treatment. There is a grievous gap between the explosion of knowledge in neuroscience and conceptually novel treatments for our patients. Translational Psychiatry bridges this gap by fostering and highlighting the pathway from discovery to clinical applications, healthcare and global health. We view translation broadly as the full spectrum of work that marks the pathway from discovery to global health, inclusive. The steps of translation that are within the scope of Translational Psychiatry include (i) fundamental discovery, (ii) bench to bedside, (iii) bedside to clinical applications (clinical trials), (iv) translation to policy and health care guidelines, (v) assessment of health policy and usage, and (vi) global health. All areas of medical research, including — but not restricted to — molecular biology, genetics, pharmacology, imaging and epidemiology are welcome as they contribute to enhance the field of translational psychiatry.
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