Identification of conserved proteomic networks in neurodegenerative dementia

Swarup, Vivek; Chang, Timothy S.; Duong, Duc M.; Dammer, Eric B.; Lah, James J.; Johnson, Erik C. B.; Seyfried, Nicholas T.; Levey, Aĺlan I.; Geschwind, Daniel H.

doi:10.1101/825802

Cited by 7 publications

(6 citation statements)

References 151 publications

(139 reference statements)

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“…1g,h). Activation of cGAS-STING was further analyzed in previously published microarray profiles of hippocampi from 3-, 6-, 9-and 12-month-old P301S transgenic mice 17 . IRF and ISRE TF motifs were enriched in DEGs associated with tauopathy (Extended Data Fig.…”

Section: Cgas-sting Is Activated In Tau Transgenic Mice and Human Admentioning

confidence: 99%

Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience

et al. 2023

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Pathological hallmarks of Alzheimer’s disease (AD) precede clinical symptoms by years, indicating a period of cognitive resilience before the onset of dementia. Here, we report that activation of cyclic GMP–AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of Cgas in mice with tauopathy diminished the microglial IFN-I response, preserved synapse integrity and plasticity and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation increased, while activation of IFN-I decreased, the neuronal MEF2C expression network linked to cognitive resilience in AD. Pharmacological inhibition of cGAS in mice with tauopathy enhanced the neuronal MEF2C transcriptional network and restored synaptic integrity, plasticity and memory, supporting the therapeutic potential of targeting the cGAS–IFN–MEF2C axis to improve resilience against AD-related pathological insults.

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Section: Cgas-sting Is Activated In Tau Transgenic Mice and Human Admentioning

confidence: 99%

Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience

et al. 2023

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“…Considering that genes do not operate along, but rather within signaling pathways and networks, we and others have shown that better understanding of disease mechanisms can be achieved through gene network analysis [31][32][33] . Therefore, we scrutinized rare variants within a network framework, focusing on co-expression network analysis performed in PSP post mortem brain that had previously identified a brain co-expression module, C1, which was conserved at the protein interaction level and enriched for common variants in PSP 34 .…”

Section: Rare Snvs/indels and Network Analysismentioning

confidence: 99%

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy

Wang,

Chang,

Dombroski

et al. 2023

Preprint

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Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. We performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), small insertions/deletions (indels), and structural variants (SVs) in a cohort of 1,718 individuals with PSP and 2,944 control subjects. Analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and also uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. In contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele and the ε4 allele to be protective, a pattern similar to the association pattern observed in age-related macular degeneration (AMD) but the opposite observed for Alzheimer's disease (AD). Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. We also observed seven common SVs associated with PSP on the H1/H2 haplotype region (17q21.31) and in a few other loci: IGH, PCMT1, CYP2A13, and SMCP. Particularly, in the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73x10-3) in PSP. Through WGS, we significantly refine our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

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“…To understand how neural‐immune‐associated genes and pathways contribute to neurodegenerative disease pathophysiology, Rexach and colleagues conducted systematic functional genomic analyses of microglia and bulk tissue from mouse and human models of AD, FTD, and PSP 50 . An earlier bulk tissue RNA sequencing (RNAseq) study by the same team revealed that downregulated microglial gene expression trajectories were likely obscured by a general disease‐related upregulation of microglia 51,52 . Accordingly, the team designed a study that would reveal both upregulated and downregulated signaling pathways within microglia, to enable more precise identification of stage‐ and pathology‐associated microglial states.…”

Section: Introductionmentioning

confidence: 99%

Novel avenues of tau research

Sexton,

Bitan,

Bowles

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONThe pace of innovation has accelerated in virtually every area of tau research in just the past few years.METHODSIn February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co‐organized and co‐sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation.RESULTSRepresenting academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research.DISCUSSIONThe virtual meeting provided an opportunity to foster cross‐sector collaboration and partnerships as well as a forum for updating colleagues on research‐advancing tools and programs that are steadily moving the field forward.

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Identification of conserved proteomic networks in neurodegenerative dementia

Cited by 7 publications

References 151 publications

Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience

Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy

Novel avenues of tau research

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