Recombinant BRICHOS chaperone domains delivered to mouse brain parenchyma by focused ultrasound and microbubbles are internalized by hippocampal and cortical neurons.
Adaptor Proteins, Signal Transducing
/ metabolism
Amyloid beta-Peptides
/ metabolism
Animals
Blood-Brain Barrier
/ metabolism
Brain
/ metabolism
Female
Hippocampus
/ metabolism
Membrane Proteins
/ metabolism
Mice, Inbred C57BL
Microbubbles
Molecular Chaperones
/ metabolism
Neurons
/ metabolism
Peptide Fragments
/ metabolism
Alzheimer's disease
Aβ
BRICHOS
Blood-brain barrier
Focused ultrasound
Journal
Molecular and cellular neurosciences
ISSN: 1095-9327
Titre abrégé: Mol Cell Neurosci
Pays: United States
ID NLM: 9100095
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
06
11
2019
revised:
30
04
2020
accepted:
02
05
2020
pubmed:
12
5
2020
medline:
4
3
2021
entrez:
12
5
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32389804
pii: S1044-7431(20)30121-4
doi: 10.1016/j.mcn.2020.103498
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Amyloid beta-Peptides
0
Membrane Proteins
0
Molecular Chaperones
0
Peptide Fragments
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
103498Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest Authors declare no conflict of interest.