Peripheral administration of human recombinant ApoJ/clusterin modulates brain beta-amyloid levels in APP23 mice.
Alzheimer Disease
/ metabolism
Amyloid beta-Peptides
/ metabolism
Amyloid beta-Protein Precursor
/ genetics
Animals
Brain
/ drug effects
Cerebral Amyloid Angiopathy
/ metabolism
Clusterin
/ administration & dosage
Encephalitis
/ metabolism
HEK293 Cells
Humans
Lipoproteins, HDL
/ administration & dosage
Mice, Transgenic
Peptide Fragments
/ metabolism
Recombinant Proteins
/ administration & dosage
APP23
Alzheimer’s disease
ApoJ
Apolipoprotein J
Clusterin
Reconstituted HDL
Journal
Alzheimer's research & therapy
ISSN: 1758-9193
Titre abrégé: Alzheimers Res Ther
Pays: England
ID NLM: 101511643
Informations de publication
Date de publication:
10 05 2019
10 05 2019
Historique:
received:
19
12
2018
accepted:
23
04
2019
entrez:
12
5
2019
pubmed:
12
5
2019
medline:
10
5
2020
Statut:
epublish
Résumé
ApoJ/clusterin is a multifunctional protein highly expressed in the brain. The implication of ApoJ in β-amyloid (Aβ) fibrillization and clearance in the context of Alzheimer's disease has been widely studied, although the source and concentration of ApoJ that promotes or inhibits Aβ cerebral accumulation is not clear yet. ApoJ is abundant in plasma and approximately 20% can appear bound to HDL-particles. In this regard, the impact of plasmatic ApoJ and its lipidation status on cerebral β-amyloidosis is still not known. Hence, our main objective was to study the effect of a peripheral increase of free ApoJ or reconstituted HDL particles containing ApoJ in an experimental model of cerebral β-amyloidosis. Fourteen-month-old APP23 transgenic mice were subjected to subchronic intravenous treatment with rHDL-rApoJ nanodiscs or free rApoJ for 1 month. Aβ concentration and distribution in the brain, as well as Aβ levels in plasma and CSF, were determined after treatments. Other features associated to AD pathology, such as neuronal loss and neuroinflammation, were also evaluated. Both ApoJ-based treatments prevented the Aβ accumulation in cerebral arteries and induced a decrease in total brain insoluble Aβ Our results demonstrate that an increase in circulating human rApoJ induces a reduction of insoluble Aβ and CAA load in the brain of APP23 mice. Thus, our study suggests that peripheral interventions, based on treatments with multifunctional physiological chaperones, offer therapeutic opportunities to regulate the cerebral Aβ load.
Sections du résumé
BACKGROUND
ApoJ/clusterin is a multifunctional protein highly expressed in the brain. The implication of ApoJ in β-amyloid (Aβ) fibrillization and clearance in the context of Alzheimer's disease has been widely studied, although the source and concentration of ApoJ that promotes or inhibits Aβ cerebral accumulation is not clear yet. ApoJ is abundant in plasma and approximately 20% can appear bound to HDL-particles. In this regard, the impact of plasmatic ApoJ and its lipidation status on cerebral β-amyloidosis is still not known. Hence, our main objective was to study the effect of a peripheral increase of free ApoJ or reconstituted HDL particles containing ApoJ in an experimental model of cerebral β-amyloidosis.
METHODS
Fourteen-month-old APP23 transgenic mice were subjected to subchronic intravenous treatment with rHDL-rApoJ nanodiscs or free rApoJ for 1 month. Aβ concentration and distribution in the brain, as well as Aβ levels in plasma and CSF, were determined after treatments. Other features associated to AD pathology, such as neuronal loss and neuroinflammation, were also evaluated.
RESULTS
Both ApoJ-based treatments prevented the Aβ accumulation in cerebral arteries and induced a decrease in total brain insoluble Aβ
CONCLUSIONS
Our results demonstrate that an increase in circulating human rApoJ induces a reduction of insoluble Aβ and CAA load in the brain of APP23 mice. Thus, our study suggests that peripheral interventions, based on treatments with multifunctional physiological chaperones, offer therapeutic opportunities to regulate the cerebral Aβ load.
Identifiants
pubmed: 31077261
doi: 10.1186/s13195-019-0498-8
pii: 10.1186/s13195-019-0498-8
pmc: PMC6511153
doi:
Substances chimiques
Amyloid beta-Peptides
0
Amyloid beta-Protein Precursor
0
CLU protein, human
0
Clusterin
0
Lipoproteins, HDL
0
Peptide Fragments
0
Recombinant Proteins
0
amyloid beta-protein (1-40)
0
amyloid beta-protein (1-42)
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
42Subventions
Organisme : Instituto de Salud Carlos III
ID : PI17/00275
Pays : International
Organisme : Instituto de Salud Carlos III
ID : PI13/00364
Pays : International
Organisme : Instituto de Salud Carlos III
ID : RD16/0019/0021
Pays : International
Organisme : Fundació la Marató de TV3
ID : 40/U/2014
Pays : International
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