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Biochem J. 2016 Oct 15;473(20):3683-3704. Epub 2016 Aug 11.

Dementia-related Bri2 BRICHOS is a versatile molecular chaperone that efficiently inhibits Aβ42 toxicity in Drosophila.

Author information

1
School of Natural Sciences and Health, Tallinn University, Narva mnt 29, 101 20 Tallinn, Estonia.
2
Munich Center for Integrated Protein Science, Department Chemie, Technische Universität München, 85747 Garching, Germany.
3
Neuronal Oscillations Laboratory, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Retzius väg 8, 17177 Stockholm, Sweden.
4
Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, 141 57 Huddinge, Sweden.
5
Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, 141 57 Huddinge, Sweden Department of Physical Organic Chemistry, Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
6
Neuronal Oscillations Laboratory, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Retzius väg 8, 17177 Stockholm, Sweden German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen St. 17, 81377 Munich, Germany.
7
School of Natural Sciences and Health, Tallinn University, Narva mnt 29, 101 20 Tallinn, Estonia Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, 141 57 Huddinge, Sweden Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Box 7011, 750 07 Uppsala, Sweden.

Abstract

Formation of fibrils of the amyloid-β peptide (Aβ) is suggested to play a central role in neurodegeneration in Alzheimer's disease (AD), for which no effective treatment exists. The BRICHOS domain is a part of several disease-related proproteins, the most studied ones being Bri2 associated with familial dementia and prosurfactant protein C (proSP-C) associated with lung amyloid. BRICHOS from proSP-C has been found to be an efficient inhibitor of Aβ aggregation and toxicity, but its lung-specific expression makes it unsuited to target in AD. Bri2 is expressed in the brain, affects processing of Aβ precursor protein, and increased levels of Bri2 are found in AD brain, but the specific role of its BRICHOS domain has not been studied in vivo Here, we find that transgenic expression of the Bri2 BRICHOS domain in the Drosophila central nervous system (CNS) or eyes efficiently inhibits Aβ42 toxicity. In the presence of Bri2 BRICHOS, Aβ42 is diffusely distributed throughout the mushroom bodies, a brain region involved in learning and memory, whereas Aβ42 expressed alone or together with proSP-C BRICHOS forms punctuate deposits outside the mushroom bodies. Recombinant Bri2 BRICHOS domain efficiently prevents Aβ42-induced reduction in γ-oscillations in hippocampal slices. Finally, Bri2 BRICHOS inhibits several steps in the Aβ42 fibrillation pathway and prevents aggregation of heat-denatured proteins, indicating that it is a more versatile chaperone than proSP-C BRICHOS. These findings suggest that Bri2 BRICHOS can be a physiologically relevant chaperone for Aβ in the CNS and needs to be further investigated for its potential in AD treatment.

KEYWORDS:

Alzheimer's disease; amyloid-β; model organisms; molecular chaperones; protein misfolding

PMID:
27514716
DOI:
10.1042/BCJ20160277
[Indexed for MEDLINE]

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