BioModelsEsraa GabalNon-curatedconstraint-based modelL3V1Not Peer Reviewedhttps://www.ebi.ac.uk/biomodels/MODEL2606020001falseBioModelshttps://github.com/BaloniLab/iMiceBrainModelsSBMLiMiceBrain (mouse brain specific GEM)2026MODEL2606020001Esraa GabalEsraa Gabal, Thi Kim Oanh Nguyen, Tetiana Kovalenko, Noa Rappaport, Cory Funk, Priyanka Baloni, Eugenia Trushinahttps://github.com/BaloniLab/iMiceBrain, Alzheimer’s disease (AD), the most prevalent form of dementia, involves convergent pathological processes, including lipid dysregulation, mitochondrial dysfunction, neuroinflammation, and metabolic failure. Single-pathway therapies have proven largely ineffective in advanced disease. Here, we investigate CP2, a blood-brain barrier-penetrating small molecule that weakly inhibits mitochondrial complex I (mtCI) to engage adaptive stress signaling. Previous studies in female APP/PS1 mice, treated after the onset of neurodegeneration, showed that CP2 produces robust benefits through a coordinated pleiotropic mechanism, preserving synaptic integrity, improving proteostasis, reducing neuroinflammation, improving mitochondrial function, and restoring metabolic and energy homeostasis in brain and periphery. Here, we demonstrate that CP2 treatment in APP/PS1 mice initiated at 19 months of age still activates multifaceted neuroprotective mechanisms. Targeted metabolomics and lipidomics reveal CP2-driven remodeling of cholesterol and sphingolipid metabolism along with enhanced β-oxidation and pyruvate flux. Integrating transcriptomics with iMiceBrain, a novel genome-scale metabolic reconstruction of the mouse brain, we demonstrate that CP2 drives broad metabolic reprogramming of lipid and energy pathways with enhanced mitochondrial substrate flexibility. These findings establish mtCI modulation as a safe and effective strategy to restore metabolic resilience in advanced AD.. null, null. 1School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA 2Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA 3Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA 4Institute for Systems Biology, Seattle, WA 98109, USA 5Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USAegabal@purdue.eduPurdue UniversityUsing a fluorescent differential display (FDD) technique, a novel cDNA was identified by screening for gene expressed differentially between the Dunn osteosarcoma cell line and the LM8 cell line, an isolated variant of the Dunn cell line that has high metastatic potential to the lung. Molecular cloning of the cDNA revealed the clone has similarity to a bacterial fermentation enzyme, the citrate lyase beta-subunit (CL-beta). Northern blot and competitive reverse transcription-PCR (RT-PCR) analysis revealed up-regulation of the gene in the LM8 cell line. An RNA Master blot indicated that the mRNA encoding CL-beta is expressed abundantly in murine heart, liver, and kidney. A human expressed sequence tag (EST) database search suggested that a similar cDNA is expressed in humans. A gene with identical sequence is located on chromosome 13 in the genome database (Sanger centre, UK). These data suggest that a citrate fermentation pathway may exist in eukaryotes including mammals.Molecular cloning of novel mouse and human putative citrate lyase beta-subunit.Morikawa J J, Nishimura Y Y, Uchida A A, Tanaka T TfalseiMiceBrain (mouse brain-specific GEM)iMiceBrain is a novel genome-scale metabolic model of mouse brain. It was developed as a consensus of metabolic reconstruction draft developed by mCADRE, rFASTACOROMICS, ftINIT, and 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