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  Glial and vascular contributions to neurodegenerative diseases
Network analysis of mouse brain
proteomes resolves molecular and cellular endophenotypes of aging and Aβ pathology Srikant Rangaraju, Kyla Langdon1, Sruti Rayaprolu1, Ruth Nelson1, Asiah McWhorter1, Hailian Xiao1, Duc Duong2, Aditya Natu1, Ananthramanan Shantaraman2, Eric Dammer2, Nicholas T Seyfried2, Srikant Rangaraju1
1Department of Neurology, Emory University, Atlanta GA, USA, 2Department of Biochemistry, Emory University, Atlanta GA, USA
 Background: Human post-mortem brain ‘omics’ studies have identified novel molecular mechanisms, cellular endophenotypes and potential targets in Alzheimer’s disease (AD). The therapeutic/biomarker pipeline to translate these findings to patients requires validation and modulation in pre-clinical models of AD pathology; we used a proteomic discovery approach identifying age/Aβ-pathology-related changes in brain models.
Materials/Methods: Brain was collected: wild-type and 5xFAD mice, aged 1.8, 3, 6, 10 and 14 months of age (equal males and females, total N=86), and used for quantitative proteomics using tandem mass tag mass spectrometry (TMT-MS). WeiGhted Coexpression Network Analysis (WGCNA) of batch-adjusted brain proteomic data was performed to identify modules of co-expressed proteins. We performed analyses of enriched gene ontologies, brain cell type-specific markers, module-trait relationships with age, sex and genotype as variables.
Results: We quantified >8,000 proteins across 86 brain samples. Aβ, APP, APOE and TREM2 showed age-dependent increase with pathological progression in 5xFAD mice. WGCNA identified 51 protein modules, of which 23 showed age-dependent genotypeindependent effects while 24 showed age- and genotype-dependent effects, and only 1 module showed isolated genotype-dependent changes. Microglial, metabolism and immune modules increased with age but were exaggerated by Aβ pathology particularly beyond 6 months. mRNA transcription/processing, protein translation, post-translational modifications showed age-dependent decline independent of genotype. Mitochondrial proteins, particularly ATP synthetic machinery, showed a pronounced decline with age only in 5xFAD mice. Progressive Aβ pathology increased microglial, astrocyte and endothelial proteins while decreasing neuronal/synaptic proteins.
Conclusion: Proteomic analysis of mouse bulk brain tissues reveals robust dysfunctions in mRNA metabolism, protein synthesis and synaptic machinery with age, independent of Aβ pathology. Progressive Aβ pathology accelerates age-related synaptic dysfunction and induces mitochondrial dysfunction. Age-related microglial/ immune activation is exaggerated by Aβ pathology.
82 • ISMND 2022

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