title: Specific suppression of microgliosis cannot circumvent the severe neuropathology in peroxisomal β-oxidation-deficient mice.
abstract: An important hallmark of various neurodegenerative disorders is the proliferation and activation of microglial cells, the resident immune cells of the central nervous system (CNS). Mice that lack multifunctional protein-2 (MFP2), the key enzyme in peroxisomal β-oxidation, develop excessive microgliosis that positively correlates with behavioral deficits whereas no neuronal loss occurs. However, the precise contribution of neuroinflammation to the fatal neuropathology of MFP2 deficiency remains largely unknown. Here, we first attempted to suppress the inflammatory response by administering various anti-inflammatory drugs but they failed to reduce microgliosis. Subsequently, Mfp2-/-mice were treated with the selective colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 as microglial proliferation and survival is dependent on CSF1R signaling. This resulted in the elimination of >95% of microglia from control mice but only 70% of the expanded microglial population from Mfp2-/-mice. Despite microglial diminution in Mfp2-/-brain, inflammatory markers remained unaltered and residual microglia persisted in a reactive state. CSF1R inhibition did not prevent neuronal dysfunction, cognitive decline and clinical deterioration of Mfp2-/-mice. Collectively, the unaltered inflammatory profile despite suppressed microgliosis concurrent with persevering clinical decline strengthens our hypothesis that neuroinflammation importantly contributes to the Mfp2-/-phenotype.
authors.affiliation: KU Leuven - University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Cell Metabolism, B-3000 Leuven, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Beckers
authors.affiliation: KU Leuven - University of Leuven, Faculty of Psychology and Educational Sciences, Biological Psychology, B-3000 Leuven, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Stroobants
authors.affiliation: KU Leuven - University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Cell Metabolism, B-3000 Leuven, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Verheijden
authors.affiliation: Plexxikon Inc., Berkeley, CA 94710, USA.
authors.forename: B
authors.initials: B
authors.lastname: West
authors.affiliation: KU Leuven - University of Leuven, Faculty of Psychology and Educational Sciences, Biological Psychology, B-3000 Leuven, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: D'Hooge
authors.affiliation: KU Leuven - University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Cell Metabolism, B-3000 Leuven, Belgium. Electronic address: myriam.baes@kuleuven.be.
authors.forename: M
authors.initials: M
authors.lastname: Baes
mesh_terms: D000161:Acoustic Stimulation; D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000943:Antigens, Differentiation / Q000378:metabolism; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000150:complications / Q000235:genetics / Q000473:pathology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects / Q000235:genetics; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005911:Gliosis / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D053580:Muscle Strength / Q000187:drug effects / Q000235:genetics; D064029:Peroxisomal Multifunctional Protein-2 / Q000172:deficiency* / Q000235:genetics; D012720:Severity of Illness Index
chemical_list: C491049:Aif1 protein, mouse; D000893:Anti-Inflammatory Agents; D000943:Antigens, Differentiation; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; C036763:monocyte-macrophage differentiation antigen; C491288:Hsd17b4 protein, mouse; D064029:Peroxisomal Multifunctional Protein-2
keywords: Behavior; Cognition; Microglia; Neuroinflammation; Neuronal transmission; Peroxisomal beta-oxidation