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Neuronal Necroptosis Drives Neuroinflammation and Cognitive Decline Independent of Neuronal Cell Death

ABSTRACT: This study investigates transcriptomic changes in a novel neuron-specific Mlkl knockin (nMlkl-KI) mouse model following tamoxifen-induced MLKL expression in neurons. Mlkl-KI mice were generated on a C57BL/6J background using a transgene construct containing 3xFLAG-tagged Mlkl cDNA inserted into the Rosa26 locus with a loxP-flanked stop cassette. Hemizygous Mlkl-KI females were crossed with homozygous Slick-H-Cre (Thy1-CreERT2-EYFP) males to produce mice expressing MLKL selectively in neurons upon tamoxifen induction. At 45 days of age, mice were treated with tamoxifen (60 mg/kg, intraperitoneally) or corn oil for 5 consecutive days. Brain cortex tissue was collected and RNA was extracted for sequencing. At 12-months of age, nMlkl-KI mice exhibited significant cognitive impairment compared to control mice as measured by a continuous homecage discrimination learning with the Noldus PhenoTyper. Unbiased stereological analysis revealed no loss in neuronal number in the cortex and hippocampus, suggesting neuronal dysfunction rather than neuronal death was responsible for the reduced cognition observed in the nMlkl-KI mice. Transcriptomic analysis of the cortex revealed an upregulation of pathways associated with age-related neurodegenerative diseases as well as chemokine and TNF signaling in the nMlkl-KI mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE304069 | GEO | 2025/07/30

REPOSITORIES: GEO

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Project description:Thiele2013 - Cerebral cortex neuronal cells The model of cerebral cortex neuronal cells metabolism is derived from the community-driven global reconstruction of human metabolism (version 2.02, MODEL1109130000 ). This model is described in the article: A community-driven global reconstruction of human metabolism. Thiele I, et al . Nature Biotechnology Abstract: Multiple models of human metabolism have been reconstructed, but each represents only a subset of our knowledge. Here we describe Recon 2, a community-driven, consensus 'metabolic reconstruction', which is the most comprehensive representation of human metabolism that is applicable to computational modeling. Compared with its predecessors, the reconstruction has improved topological and functional features, including ~2x more reactions and ~1.7x more unique metabolites. Using Recon 2 we predicted changes in metabolite biomarkers for 49 inborn errors of metabolism with 77% accuracy when compared to experimental data. Mapping metabolomic data and drug information onto Recon 2 demonstrates its potential for integrating and analyzing diverse data types. Using protein expression data, we automatically generated a compendium of 65 cell type-specific models, providing a basis for manual curation or investigation of cell-specific metabolic properties. Recon 2 will facilitate many future biomedical studies and is freely available at http://humanmetabolism.org/. This model is hosted on BioModels Database and identified by: MODEL1310110033 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Neuronal Necroptosis Drives Neuroinflammation and Cognitive Decline Independent of Neuronal Cell Death

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