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SELENOK-Dependent CD36 Palmitoylation Regulates Microglial Functions and Aβ Phagocytosis

ABSTRACT: Amyloid-beta (Aβ) is a key factor in the onset and progression of Alzheimer's disease (AD). Selenium (Se) compounds show promise in AD treatment. Here, we reveal that selenoprotein K (SELENOK), a selenoprotein involved in immune regulation and potentially related to AD pathology, plays a critical role in microglial immune response, migration, and phagocytosis. In vivo and in vitro studies corroborate that SELENOK deficiency inhibits microglial Aβ phagocytosis, exacerbating cognitive deficits in 5xFAD mice, which are reversed by SELENOK overexpression. Mechanistically, SELENOK is involved in CD36 palmitoylation through DHHC6, regulating CD36 localization to microglial plasma membranes and thus impacting Aβ phagocytosis. CD36 palmitoylation is reduced in the brains of AD patients and mice. Se supplementation promotes SELENOK expression and CD36 palmitoylation, enhancing microglial Aβ phagocytosis and mitigating AD progression. We have identified the regulatory mechanisms from Se-dependent selenoproteins to Aβ pathology, providing novel insights into potential therapeutic strategies involving Se and selenoproteins.

ORGANISM(S): Mus musculus

PROVIDER: GSE255034 | GEO | 2024/02/29

REPOSITORIES: GEO

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Project description:Background: The p38 alpha mitogen-activated protein kinase (p38a) pathway is linked to both innate and adaptive immune responses, and as such, is currently under active investigation as a target for drug development in the context of Alzheimer’s disease (AD) and other conditions with neuroinflammatory dysfunction. While preclinical data has shown that p38a inhibition can protect against AD-associated neuropathology, the underlying mechanisms are only partially elucidated. Inhibitors of p38a may provide benefit via modulation of microglial-associated neuroinflammatory responses that contribute to the development of AD pathology. The present study tests this hypothesis by knocking out microglial p38a and assessing early-stage pathological changes. Materials and methods: Conditional knockout of microglial p38a was accomplished in 5-month-old C57BL/6J wild-type and amyloidogenic AD model (APPswe/PS1dE9) mice using a tamoxifen-inducible Cre/loxP system. Beginning at 7.5 months of age, animals underwent behavioral assessment on the open field and radial arm water maze tests, followed by collection of cortical and hippocampal tissues at 11 months. Additional endpoint measures included microglial RNA-seq analysis, quantification of pro-inflammatory cytokines, assessment of amyloid burden and plaque deposition, and characterization of microglia-plaque dynamics using a combination of ELISA, immunohistochemical, and immunofluorescent techniques. Results: Loss of microglial p38a did not alter behavioral outcomes, pro-inflammatory cytokine levels, or overall amyloid plaque burden. However, this manipulation did significantly increase hippocampal levels of soluble Abeta42 and reduce colocalization of Iba1 and 6E10 in a subset microglia in close proximity to plaques, indicating that p38a suppression may alter microglial phagocytosis. Conclusion: The data presented here suggest that rather than reducing inflammation per se, the net effect of microglial p38a inhibition in the context of AD-type amyloid pathology could be an alteration of phagocytosis and/or plaque deposition. Additionally, these results support future investigations of microglial p38a signaling at different stages of disease, as well as its relationship to phagocytic processes in this particular cell-type.

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SELENOK-Dependent CD36 Palmitoylation Regulates Microglial Functions and Aβ Phagocytosis

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