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Peripheral administration of human recombinant ApoJ/clusterin modulates brain beta-amyloid levels in APP23 mice
Fernández de Retana Alda, Sofía (Hospital Universitari Vall d'Hebron)
Marazuela, Paula (Hospital Universitari Vall d'Hebron)
Solé Piñol, Montserrat (Hospital Universitari Vall d'Hebron)
Colell, Guillem (Hospital Universitari Vall d'Hebron)
Bonaterra, Anna (Hospital Universitari Vall d'Hebron)
Sánchez Quesada, José Luis (Hospital de la Santa Creu i Sant Pau)
Montaner, Joan (Vall d'Hebron Institut de Recerca)
Maspoch Comamala, Daniel (Institut Català de Nanociència i Nanotecnologia)
Cano Sarabia, Antonia María (Institut Català de Nanociència i Nanotecnologia)
Hernández Guillamón, María del Mar (Vall d'Hebron Institut de Recerca)

Data: 2019
Resum: 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 levels. The peripheral treatment with rApoJ also induced an increase in the Aβ levels in CSF, whereas the concentration remained unaltered in plasma. At all the endpoints studied, the lipidation of rApoJ did not enhance the protective properties of free rApoJ. The effects obtained after subchronic treatment with free rApoJ were accompanied by a reduction in hippocampal neuronal loss and an enhancement of the expression of a phagocytic marker in microglial cells surrounding Aβ deposits. Finally, despite the activation of this phagocytic phenotype, treatments did not induce a global neuroinflammatory status. In fact, free rApoJ treatment was able to reduce the levels of interleukin-17 (IL17) and keratinocyte chemoattractant (KC) chemokine in the brain. 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.
Nota: Altres ajuts: Fundació La Marató de TV3 [40/U/2014]
Nota: Número d'acord de subvenció ISCIII/PI17/00275
Nota: Número d'acord de subvenció ISCIII/PI14/01134
Nota: Número d'acord de subvenció ISCIII/PI13/00364
Nota: Número d'acord de subvenció ISCIII/RD16/0019/0021
Nota: Número d'acord de subvenció ISCIII/CPII17/00010
Nota: Número d'acord de subvenció MINECO/SEV-2013-0295
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès.
Document: article ; recerca ; publishedVersion
Matèria: Clusterin ; Apolipoprotein J ; ApoJ ; APP23 ; Reconstituted HDL ; Alzheimer's disease
Publicat a: Alzheimer's research and therapy, Vol. 11 (May 2019) , art. 42, ISSN 1758-9193

DOI: 10.1186/s13195-019-0498-8
PMID: 31077261


17 p, 9.8 MB

El registre apareix a les col·leccions:
Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències > Institut Català de Nanociència i Nanotecnologia (ICN2)
Articles > Articles de recerca
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 Registre creat el 2019-07-02, darrera modificació el 2019-08-01



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