The BRICHOS domain is found in human precursor proteins associated with cancer, dementia (Bri2) and amyloid lung disease (proSP-C). Recombinant human (rh) proSP-C and Bri2 BRICHOS domains delay amyloid-β peptide (Aβ) fibril formation and reduce associated toxicity in vitro and their overexpression reduces Aβ neurotoxicity in animal models of Alzheimer's disease. After intravenous administration in wild-type mice, rh Bri2, but not proSP-C, BRICHOS was detected in the brain parenchyma, suggesting that Bri2 BRICHOS selectively bypasses the blood-brain barrier (BBB). Here, our objective was to increase the brain delivery of rh proSP-C (trimer of 18 kDa subunits) and Bri2 BRICHOS (monomer to oligomer of 15 kDa subunits) using focused ultrasound combined with intravenous microbubbles (FUS + MB), which enables targeted and transient opening of the BBB. FUS + MB was targeted to one hemisphere of wild type mice and BBB opening in the hippocampal region was confirmed by magnetic resonance imaging. Two hours after FUS + MB brain histology showed no signs of tissue damage and immunohistochemistry showed abundant delivery to the brain parenchyma in 13 out of 16 cases given 10 mg/kg of proSP-C or Bri2 BRICHOS domains. The Bri2, but not proSP-C BRICHOS domain was detected also in the non-targeted hemisphere. ProSP-C and Bri2 BRICHOS domains were taken up by a subset of neurons in the hippocampus and cortex, and were detected to a minor extent in early endosomes. These results indicate that rh Bri2, but not proSP-C, BRICHOS, can be efficiently delivered into the mouse brain parenchyma and that both BRICHOS domains can be internalized by cell-specific mechanisms.

中文翻译：

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通过聚焦超声传递到小鼠脑实质的重组BRICHOS分子伴侣域和微泡被海马和皮层神经元内在化。

在与癌症，痴呆症（Bri2）和淀粉样肺病（proSP-C）相关的人类前体蛋白中发现了BRICHOS域。重组人（rh）proSP-C和Bri2 BRICHOS域在体外可延缓淀粉样β肽（Aβ）的原纤维形成并降低相关毒性，而它们的过度表达可降低阿尔茨海默氏病动物模型的Aβ神经毒性。在野生型小鼠rh Bri2（而非proSP-C）中静脉内给药后，在脑实质中检测到BRICHOS，这表明Bri2 BRICHOS选择性绕过了血脑屏障（BBB）。在这里，我们的目标是使用聚焦超声结合静脉内微泡（FUS + MB）来增加rh proSP-C（18 kDa亚基的三聚体）和Bri2 BRICHOS（15 kDa亚基的单体到寡聚体）的大脑传递，可以有针对性地短暂打开血脑屏障。FUS + MB靶向野生型小鼠的一个半球，并通过磁共振成像证实了海马区的BBB开放。FUS + MB后两小时，脑组织学检查未见组织损伤迹象，免疫组化显示16例给予ProSP-C或Bri2 BRICHOS结构域10 mg / kg的病例中有13例充分递送至脑实质。在非目标半球中也检测到Bri2，但未检测到proSP-C BRICHOS域。ProSP-C和Bri2 BRICHOS结构域被海马和皮层中的一部分神经元吸收，并在早期的内体中被少量检测到。这些结果表明，rh Bri2而非proSP-C，BRICHOS，