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

[Background]: ApoJ/clusterin is a multifunctional protein highly expressed in the brain. The implication of ApoJ in βamyloid (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 βamyloidosis.[Methods]: Fourteen-month-old APP23 transgenic mice were subjected to subchronic intravenous treatment with rHDLrApoJ 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 Aβ42 levels. The peripheral treatment with rApoJ also induced an increase in the Aβ40 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.This work has been funded by Instituto de Salud Carlos III (ISCIII) [PI17/00275, PI14/01134, and PI13/00364], co-financed by the European Regional Development Fund (FEDER), and Fundació La Marató de TV3 [40/U/2014]. The Neurovascular Research Laboratory is part of the INVICTUS+ network, ISCIII, Spain [RD16/0019/0021]. J.L.S-Q is a member of the CIBER of Diabetes and Metabolism (CIBERDEM), ISCIII, Spain. M.H-G is supported by the Miguel Servet programme, ISCIII, Spain [CPII17/00010]. ICN2 acknowledges the support of the Spanish MINECO through the Severo Ochoa Centers of Excellence Programme, under Grant SEV-2013-0295.Peer reviewe