RESUMEN

Inflammation in the central nervous system can impair the function of neuronal mitochondria and contributes to axon degeneration in the common neuroinflammatory disease multiple sclerosis (MS). Here we combine cell-type-specific mitochondrial proteomics with in vivo biosensor imaging to dissect how inflammation alters the molecular composition and functional capacity of neuronal mitochondria. We show that neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal ATP deficiency, which precedes mitochondrial oxidation and calcium overload. This axonal energy deficiency is associated with impaired electron transport chain function, but also an upstream imbalance of tricarboxylic acid (TCA) cycle enzymes, with several, including key rate-limiting, enzymes being depleted in neuronal mitochondria in experimental models and in MS lesions. Notably, viral overexpression of individual TCA enzymes can ameliorate the axonal energy deficits in neuroinflammatory lesions, suggesting that TCA cycle dysfunction in MS may be amendable to therapy.

Asunto(s)

Esclerosis Múltiple , Enfermedades Neuroinflamatorias , Animales , Ratones , Axones/patología , Esclerosis Múltiple/patología , Neuronas/patología , Inflamación/patología

RESUMEN

The innate immune cell compartment is highly diverse in the healthy central nervous system (CNS), including parenchymal and non-parenchymal macrophages. However, this complexity is increased in inflammatory settings by the recruitment of circulating myeloid cells. It is unclear which disease-specific myeloid subsets exist and what their transcriptional profiles and dynamics during CNS pathology are. Combining deep single-cell transcriptome analysis, fate mapping, in vivo imaging, clonal analysis, and transgenic mouse lines, we comprehensively characterized unappreciated myeloid subsets in several CNS compartments during neuroinflammation. During inflammation, CNS macrophage subsets undergo self-renewal, and random proliferation shifts toward clonal expansion. Last, functional studies demonstrated that endogenous CNS tissue macrophages are redundant for antigen presentation. Our results highlight myeloid cell diversity and provide insights into the brain's innate immune system.

Asunto(s)

Sistema Nervioso Central/inmunología , Inmunidad Innata , Inflamación/inmunología , Macrófagos/citología , Células Mieloides/citología , Animales , Presentación de Antígeno , Encéfalo/inmunología , Células Dendríticas/citología , Encefalomielitis Autoinmune Experimental/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Homeostasis , Macrófagos/inmunología , Ratones Endogámicos C57BL , Ratones Transgénicos , Monocitos/citología , Células Mieloides/inmunología , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Linfocitos T/inmunología

RESUMEN

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and is triggered via abnormal accumulation of amyloid-ß peptide (Aß). Aggregated Aß is responsible for disrupting calcium homeostasis, inducing neuroinflammation, and promoting neurodegeneration. In this study, we generated curcuminoid submicron particle (CSP), which reduce the average size to ~60 nm in diameter. CSP had elevated the bioavailability in vivo and better neuroprotective effect against oligomeric Aß than un-nanosized curcuminoids in vitro. Two months of CSP consumption reversed spatial memory deficits and the loss of a calcium binding protein calbindin-D28k in the hippocampus of AD mouse model. In addition, CSP consumption lowered amyloid plaques and astrogliosis in vivo and enhanced microglial Aß phagocytosis in vitro, implying that the beneficial effects of CSP also mediated via modulating neuroinflammation and enhancing amyloid clearance. Taken together, our study demonstrated the protective effects of CSP toward ameliorating the memory impairment and pathological deficits in AD mouse model.