Blood–brain and blood–cerebrospinal fluid passage of BRICHOS domains from two molecular chaperones in mice

• Published in: The Journal of biological chemistry Vol. 294; no. 8; pp. 2606 - 5220
• Main Authors: Tambaro, Simone, Galan-Acosta, Lorena, Leppert, Axel, Chen, Gefei, Biverstål, Henrik, Presto, Jenny, Nilsson, Per, Johansson, Jan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.02.2019; American Society for Biochemistry and Molecular Biology
• Subjects: Adaptor Proteins, Signal Transducing; Amyloid beta-Peptides - metabolism; Animals; Blood-Brain Barrier - metabolism; Brain - metabolism; Cell Membrane Permeability; Intercellular Signaling Peptides and Proteins; Male; Medicin och hälsovetenskap; Membrane Proteins - administration & dosage; Membrane Proteins - blood; Membrane Proteins - cerebrospinal fluid; Mice; Mice, Inbred C57BL; Neurobiology; neurodegenerative disease; neuroscience; Peptides - administration & dosage; Peptides - blood; Peptides - cerebrospinal fluid; protein aggregation; protein assembly; protein domain; Protein Domains; protein misfolding; Pulmonary Surfactant-Associated Protein C; protein domain; neurodegenerative disease; protein assembly; protein misfolding; neuroscience; protein aggregation
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.RA118.004538

Targeting toxicity associated with β-amyloid (Aβ) misfolding and aggregation is a promising therapeutic strategy for preventing or managing Alzheimer's disease. The BRICHOS domains from human prosurfactant protein C (proSP-C) and integral membrane protein 2B (Bri2) efficiently reduce neurotoxicity associated with Aβ42 fibril formation both in vitro and in vivo. In this study, we evaluated the serum half-lives and permeability into the brain and cerebrospinal fluid (CSF) of recombinant human (rh) proSP-C and Bri2 BRICHOS domains injected intravenously into WT mice. We found that rh proSP-C BRICHOS has a longer blood serum half-life compared with rh Bri2 BRICHOS and passed into the CSF but not into the brain parenchyma. As judged by Western blotting, immunohistochemistry, and ELISA, rh Bri2 BRICHOS passed into both the CSF and brain. Intracellular immunostaining for rh Bri2 BRICHOS was observed in the choroid plexus epithelium as well as in the cerebral cortex. Our results indicate that intravenously administered rh proSP-C and Bri2 BRICHOS domains have different pharmacokinetic properties and blood–brain/blood–CSF permeability in mice. The finding that rh Bri2 BRICHOS can reach the brain parenchyma after peripheral administration may be harnessed in the search for new therapeutic strategies for managing Alzheimer's disease.