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Peripheral administration of human recombinant ApoJ/clusterin modulates brain beta-amyloid levels in APP23 mice.

ABSTRACT: BACKGROUND:ApoJ/clusterin is a multifunctional protein highly expressed in the brain. The implication of ApoJ in ?-amyloid (A?) 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 A? 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 ?-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 ?-amyloidosis. METHODS:Fourteen-month-old APP23 transgenic mice were subjected to subchronic intravenous treatment with rHDL-rApoJ nanodiscs or free rApoJ for 1?month. A? concentration and distribution in the brain, as well as A? 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 A? accumulation in cerebral arteries and induced a decrease in total brain insoluble A?42 levels. The peripheral treatment with rApoJ also induced an increase in the A?40 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 A? 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 A? 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 A? load.

SUBMITTER: de Retana SF

PROVIDER: S-EPMC6511153 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Peripheral administration of human recombinant ApoJ/clusterin modulates brain beta-amyloid levels in APP23 mice.

de Retana Sofía Fernández SF Marazuela Paula P Solé Montse M Colell Guillem G Bonaterra Anna A Sánchez-Quesada Jose Luis JL Montaner Joan J Maspoch Daniel D Cano-Sarabia Mary M Hernández-Guillamon Mar M

Alzheimer's research & therapy 20190510 1

<h4>Background</h4>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 ...[more]

PMID: 31077261

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Project description:BackgroundThe deposition of the amyloid β-peptide (Aβ) in the brain is one of the hallmarks of Alzheimer's disease (AD). It is not yet clear whether Aβ always leads to similar changes or whether it induces different features of neurodegeneration in relation to its intra- and/or extracellular localization or to its intracellular trafficking routes. To address this question, we have analyzed two transgenic mouse models: APP48 and APP23 mice. The APP48 mouse expresses Aβ1-42 with a signal sequence in neurons. These animals produce intracellular Aβ independent of amyloid precursor protein (APP) but do not develop extracellular Aβ plaques. The APP23 mouse overexpresses human APP with the Swedish mutation (KM670/671NL) in neurons and produces APP-derived extracellular Aβ plaques and intracellular Aβ aggregates.ResultsTracing of commissural neurons in layer III of the frontocentral cortex with the DiI tracer revealed no morphological signs of dendritic degeneration in APP48 mice compared to littermate controls. In contrast, the dendritic tree of highly ramified commissural frontocentral neurons was altered in 15-month-old APP23 mice. The density of asymmetric synapses in the frontocentral cortex was reduced in 3- and 15-month-old APP23 but not in 3- and 18-month-old APP48 mice. Frontocentral neurons of 18-month-old APP48 mice showed an increased proportion of altered mitochondria in the soma compared to wild type and APP23 mice. Aβ was often seen in the membrane of neuronal mitochondria in APP48 mice at the ultrastructural level.ConclusionsThese results indicate that APP-independent intracellular Aβ accumulation in APP48 mice is not associated with dendritic and neuritic degeneration but with mitochondrial alterations whereas APP-derived extra- and intracellular Aβ pathology in APP23 mice is linked to dendrite degeneration and synapse loss independent of obvious mitochondrial alterations. Thus, Aβ aggregates in APP23 and APP48 mice induce neurodegeneration presumably by different mechanisms and APP-related production of Aβ may, thereby, play a role for the degeneration of neurites and synapses.

Dataset Information

Peripheral administration of human recombinant ApoJ/clusterin modulates brain beta-amyloid levels in APP23 mice.

Publications

Peripheral administration of human recombinant ApoJ/clusterin modulates brain beta-amyloid levels in APP23 mice.

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