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 b (Ab) 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 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 wildtype 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 involved in 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. To investigat the effects of rh Bri2 BRICHOS treatment on microglial activation, we isolated cortical microglial cells from three mice from each of the four treatment groups, i.e. WT and AppNL-G-F mice treated with either PBS (veh) or rh Bri2 BRICHOS R221E, and performed bulk mRNA sequencing.

目前仍亟需可有效治疗已确诊阿尔茨海默病（Alzheimer's disease, AD）的临床策略。BRICHOS是一类可抑制淀粉样纤维形成及相关细胞毒性的分子伴侣结构域。本研究在阿尔茨海默病模型小鼠的病理症状出现7个月后，通过静脉给药方式给予重组人（recombinant human, rh）Bri2 BRICHOS R221E进行干预。AD模型小鼠每周接受两次给药、持续3个月后，经胶质纤维酸性蛋白（glial fibrillary acidic protein, GFAP）与离子钙结合衔接分子1（ionized calcium-binding adaptor molecule 1, Iba1）免疫组化检测结果显示，其β淀粉样蛋白（amyloid b, Ab）负荷显著降低，星形胶质细胞与小胶质细胞的活化状态也得到缓解。对皮层小胶质细胞的RNA测序分析表明，BRICHOS干预可使小鼠与人类中已鉴定的斑块诱导基因（包括簇集蛋白clusterin与GFAP）的表达恢复至正常水平。在年龄匹配的野生型小鼠体内，rh Bri2 BRICHOS R221E可像在AD模型小鼠中一样高效穿透血脑屏障（blood-brain barrier, BBB），但并未对AD样病理相关指标产生影响，且主要调控参与细胞形态建成与运动过程的基因表达。上述结果提示，rh Bri2 BRICHOS R221E对晚期阿尔茨海默病具有潜在治疗价值，同时证实了BRICHOS靶向淀粉样蛋白诱导病理过程的能力。为探究rh Bri2 BRICHOS干预对小胶质细胞活化的影响，我们从4个给药组的各3只小鼠中分离皮层小胶质细胞，4个给药组分别为：经磷酸盐缓冲液（phosphate buffered saline, PBS，即载体对照veh）处理的野生型小鼠、经PBS处理的AppNL-G-F AD模型小鼠、经rh Bri2 BRICHOS R221E处理的野生型小鼠，以及经rh Bri2 BRICHOS R221E处理的AppNL-G-F AD模型小鼠，随后对其开展批量mRNA测序。