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miR155 regulation of behavior, neuropathology, and cortical transcriptomics in Alzheimer's disease

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Abstract

MicroRNAs are recognized as important regulators of many facets of physiological brain function while also being implicated in the pathogenesis of several neurological disorders. Dysregulation of miR155 is widely reported across a variety of neurodegenerative conditions, including Alzheimer’s disease (AD), Parkinson’s disease, amyotrophic lateral sclerosis, and traumatic brain injury. In previous work, we observed that experimentally validated miR155 gene targets were consistently enriched among genes identified as differentially expressed across multiple brain tissue and disease contexts. In particular, we found that human herpesvirus-6A (HHV-6A) suppressed miR155, recapitulating reports of miR155 inhibition by HHV-6A in infected T-cells, thyrocytes, and natural killer cells. In earlier studies, we also reported the effects of constitutive deletion of miR155 on accelerating the accumulation of Aβ deposits in 4-month-old APP/PSEN1 mice. Herein, we complete the cumulative characterization of transcriptomic, electrophysiological, neuropathological, and learning behavior profiles from 4-, 8- and 10-month-old WT and APP/PSEN1 mice in the absence or presence of miR155. We also integrated human post-mortem brain RNA-sequences from four independent AD consortium studies, together comprising 928 samples collected from six brain regions. We report that gene expression perturbations associated with miR155 deletion in mouse cortex are in aggregate observed to be concordant with AD-associated changes across these independent human late-onset AD (LOAD) data sets, supporting the relevance of our findings to human disease. LOAD has recently been formulated as the clinicopathological manifestation of a multiplex of genetic underpinnings and pathophysiological mechanisms. Our accumulated data are consistent with such a formulation, indicating that miR155 may be uniquely positioned at the intersection of at least four components of this LOAD “multiplex”: (1) innate immune response pathways; (2) viral response gene networks; (3) synaptic pathology; and (4) proamyloidogenic pathways involving the amyloid β peptide (Aβ).

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Acknowledgements

S. G. and M. E. E. acknowledge the support of U01 AG046170 from the NIA. B. R., S. G., M. E. E., and J. T. D. acknowledge the support of 1R56AG058469, 1R01AG058469, and R21AG63968 from the NIA, and P50 AG005138 to Mary Sano. B. R. and J. T. D. acknowledge the support of U01AG061835 and R21AG063068 from the NIA. Philanthropic financial support was provided by Katherine Gehl and by the George B. Link, Jr., Foundation. DM acknowledges the support of the Alzheimer’s Association (AARGD-17-529197). The computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai also contributed to the performance of this research. The authors also acknowledge Research Computing at Arizona State University for providing computational resources that have contributed to this research. The Scott Moskowitz Foundation for Alzheimer’s Research, the Jane Martin and Stuart Katz Foundation, the Werber Family Foundation, the Sara and Gideon Gartner Foundation, the Louis B. Mayer Foundation, the, the Lady Va and Sir Deryck Maughan Foundation, the Georgianne and Dr. Reza Khatib Foundation, and the Linda Wachner Foundation provided additional support. The results published here are in part based on data obtained from the AMP-AD Knowledge Portal (https://adknowledgeportal.synapse.org/). MSBB RNA-sequencing data was generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt from Mount Sinai School of Medicine. The MAYO TCX RNAseq study data were provided by the following sources: The Mayo Clinic Alzheimers Disease Genetic Studies, led by Dr. Nilufer Ertekin-Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinsons Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimers Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimers Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinsons Research. The ROS/MAP RNAseq study data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNAseq), R01AG17917 (MAP), R01AG30146, R01AG36836 (RNAseq), RF1AG57473 (single nucleus RNAseq), U01AG46152 (ROSMAP AMP-AD, targeted proteomics), U01AG61356 (whole genome sequencing, targeted proteomics, ROSMAP AMP-AD), the Illinois Department of Public Health (ROSMAP), and the Translational Genomics Research Institute (genomic). Additional phenotypic data can be requested at www.radc.rush.edu.

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  1. Ben Readhead and Jean-Vianney Haure-Mirande contributed equally. Joel T. Dudley and Michelle E. Ehrlich are co-corresponding authors.

Authors and Affiliations

  1. Arizona State University-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, 85281, USA

    Ben Readhead & Diego Mastroeni

  2. Icahn Institute of Genomic Sciences and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Ben Readhead, Joel T. Dudley & Michelle E. Ehrlich

  3. Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Jean-Vianney Haure-Mirande, Mickael Audrain, Tomas Fanutza, Soong H. Kim, Sam Gandy & Michelle E. Ehrlich

  4. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Robert D. Blitzer

  5. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Robert D. Blitzer

  6. Alzheimer’s Disease Research Center, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Sam Gandy

  7. Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Michelle E. Ehrlich

  8. Mount Sinai Center for Cognitive Health and NFL Neurological Care, Department of Neurology, New York, NY, 10029, USA

    Sam Gandy

  9. James J. Peters VA Medical Center, 130 West Kingsbridge Road, New York, NY, 10468, USA

    Sam Gandy

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  1. Ben Readhead
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Contributions

BR, JVHM, SG, MEE, JTD designed the study. BR performed the computational analysis. JVHM, MA, TF, SK, MEE carried out the murine miR155 experiments. DM performed the human miR155 experiments. BR, JVHM, SG, MEE, JTD wrote the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Joel T. Dudley or Michelle E. Ehrlich.

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401_2020_2185_MOESM1_ESM.tiff

Absence or deficiency of miR155 does not modify the levels of human APP or synaptic markers in 8-month-old mice. Western blots and densitometric analyses of 6E10, Synapsin-1, and PSD-95 levels from brain homogenates of 8-month-old males and females WT and APP/PSEN1 mice WT, KO, or heterozygous for miR155 (TIFF 1020 kb)

401_2020_2185_MOESM2_ESM.tiff

Normalized expression of outlier log2FC genes. We observed a small subset of identified DEG with unusually large absolute log2FC (>20). Inspection of normalized gene expression indicates that results arise from comparison of groups where one group did not have any detectable expression (TIFF 159 kb)

401_2020_2185_MOESM3_ESM.tiff

Comparative transcriptomics across genotypes (a) Overlapping DEG (FDR<0.1) across main transcriptomic comparisons. Gene symbols shown in intersecting cells with overlapping DEG. (b) Comparative expression of BTG3 across the study. DEG: Differentially expressed gene, WT: Wildtype (TIFF 188 kb)

Differential gene expression analysis results (XLSX 45528 kb)

Gene set enrichment results (XLSX 961 kb)

Sample demographics of control and AD cases used for in situ hybridization studies (DOCX 18 kb)

Summary of human post-mortem brain tissue samples: Mount Sinai Brain Bank (DOCX 19 kb)

Summary of human post-mortem brain tissue samples: Religious Orders Study (DOCX 15 kb)

Summary of human post-mortem brain tissue samples: Memory Aging Project (DOCX 15 kb)

Summary of human post-mortem brain tissue samples: Mayo TCX (DOCX 16 kb)

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Readhead, B., Haure-Mirande, JV., Mastroeni, D. et al. miR155 regulation of behavior, neuropathology, and cortical transcriptomics in Alzheimer's disease. Acta Neuropathol 140, 295–315 (2020). https://doi.org/10.1007/s00401-020-02185-z

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