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静脉内伴侣治疗晚期阿尔茨海默病（AD）小鼠模型可影响淀粉样斑块负荷、反应性神经胶质增生和 AD 相关基因。

Intravenous chaperone treatment of late-stage Alzheimer´s disease (AD) mouse model affects amyloid plaque load, reactive gliosis and AD-related genes.

机构信息

Department of Medicine Huddinge, Karolinska Institutet, Huddinge, Sweden.

Division of Neurogeriatrics, Department of Neurobiology, Care Sciences & Society, Karolinska Institutet, Solna, Sweden.

出版信息

Transl Psychiatry. 2024 Oct 24;14(1):453. doi: 10.1038/s41398-024-03161-x.

DOI:10.1038/s41398-024-03161-x
PMID:39448576
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11502864/
Abstract

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.

摘要

需要有效的治疗策略来对抗已建立的阿尔茨海默病（AD）。BRICHOS 是一种分子伴侣结构域，可防止淀粉样纤维形成和相关的细胞毒性。在这项研究中，我们在病理发生后七个月开始用重组人（rh）Bri2 BRICHOS R221E 对 AD 小鼠模型进行治疗。AD 小鼠每周接受两次 rh Bri2 BRICHOS R221E 静脉注射，持续三个月，可减轻淀粉样β（Aβ）负担，并通过胶质纤维酸性蛋白（GFAP）和钙结合衔接蛋白 1（Iba1）免疫组织化学减轻星形胶质细胞和小胶质细胞增生。来自皮质小胶质细胞的 RNA 测序显示，BRICHOS 治疗可使小鼠和人类中鉴定的斑块诱导基因的表达正常化，包括载脂蛋白和 GFAP。在年龄匹配的野生型小鼠中，rh Bri2 BRICHOS R221E 像在 AD 小鼠中一样有效地穿过血脑屏障（BBB），但对 AD 样病理学的测量没有影响，主要影响影响细胞形状和运动的基因的表达。这些结果表明 rh Bri2 BRICHOS 对晚期 AD 有潜在的治疗作用，并强调了 BRICHOS 靶向淀粉样蛋白诱导的病理学的能力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce5/11502864/bcd331544e6d/41398_2024_3161_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce5/11502864/22345bdb13cb/41398_2024_3161_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce5/11502864/4884511998a0/41398_2024_3161_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce5/11502864/a8d54ef7d406/41398_2024_3161_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce5/11502864/60f47a32bc74/41398_2024_3161_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce5/11502864/4634b7c0aefa/41398_2024_3161_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce5/11502864/f16630993ba6/41398_2024_3161_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce5/11502864/bcd331544e6d/41398_2024_3161_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce5/11502864/22345bdb13cb/41398_2024_3161_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce5/11502864/bc5d5ff012d5/41398_2024_3161_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce5/11502864/4884511998a0/41398_2024_3161_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce5/11502864/a8d54ef7d406/41398_2024_3161_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce5/11502864/60f47a32bc74/41398_2024_3161_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce5/11502864/4634b7c0aefa/41398_2024_3161_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce5/11502864/f16630993ba6/41398_2024_3161_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce5/11502864/bcd331544e6d/41398_2024_3161_Fig8_HTML.jpg

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