Recombinant BRICHOS chaperone domains delivered to mouse brain parenchyma by focused ultrasound and microbubbles are internalized by hippocampal and cortical neurons

• DOI: 10.1016/j.mcn.2020.103498
• Publication Date: 2020-05-08T06:47:32Z
• Authors: L. Galan-Acosta; C. Sierra; A. Leppert; A.N. Pouliopoulos; N. Kwon; R.L. Noel; S. Tambaro; J. Presto; P. Nilsson; E.E. Konofagou; J. Johansson
• Keywords: Parenchyma

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