Gene Network Changes in Alzheimer's Disease: Potential Points for Therapeutic Intervention

Gene Network Changes in Alzheimer's Disease: Potential Points for Therapeutic Intervention

Monday, November 3, 2014

The New York Academy of Sciences

Microglia, the resident innate immune cells of the central nervous system (CNS), have emerged as critical players in normal CNS function as well as in the progression of major disorders such as Alzheimer's disease (AD). Although microglia have been traditionally categorized into either the pro-inflammatory 'M1' or the anti-inflammatory 'M2' phenotype, new studies have uncovered a previously unappreciated spectrum of microglial phenotypes involved in a range of important processes including synaptic homeostasis and neurotrophic support. In order to address whether this spectrum is altered in AD, it is first necessary to elucidate the molecular signatures underlying these microglial phenotypes. Recent efforts have therefore applied next generation sequencing techniques and approaches such as weighted gene co-expression network analysis, a systems biology method for describing the correlation patterns among genes, to better understand these signatures at the genomic level. Remarkably, the most perturbed gene networks identified in AD brains fall squarely within microglial pathways and these findings are consistent with previous genome wide association studies linking specific microglial genes to AD risk. Furthermore, parallel work examining the peripheral immune system indicates that monocytes may exhibit some of the same gene network changes, opening the possibility of developing new peripheral biomarkers. This symposium will therefore focus on the identification of microglial gene network signatures associated with AD, how these phenotypes might be modulated to alter the course of AD pathology, and how a better understanding of peripheral immune biology may lead to the development of therapeutics and peripheral biomarkers for AD.

*Reception to follow.

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Agenda

* Presentation titles and times are subject to change.


November 3, 2014

8:00 AM

Registration and Continental Breakfast

8:30 AM

Welcome and Opening Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Sean Pintchovski, PhD, Lundbeck Research USA

8:40 AM

Transcriptional Signatures of Microglia in Normal and Diseased Human Brain
Michael C. Oldham, PhD, University of California, San Francisco

9:20 AM

Multiscale Gene Network Modeling of Late-onset Alzheimer's Disease
Bin Zhang, PhD, Icahn School of Medicine at Mount Sinai

10:00 AM

Networking Coffee Break

10:30 AM

Identification of a Unique Molecular and Functional Microglia Signature in Health and Disease
Oleg Butovsky, PhD, Brigham and Women’s Hospital and Harvard Medical School

11:10 AM

Parsing Microglial Phenotypes by Comparing Chronic and Acute Inflammatory Conditions
Erik H.W.G.M. Boddeke, PhD, University Medical Center Groningen

11:50 AM

Networking Lunch Break and Poster Session

All poster presenters should stand by their posters 12:20–12:50 PM

1:00 PM

RNA-Seq Reveals a Dynamic Microglial Sensome
Joseph El Khoury, MD, Massachusetts General Hospital and Harvard Medical School

1:40 PM

Maintaining the Microglia Status Quo: CNS Signals that Determine Microglia Homeostasis
Miriam Merad, MD, PhD, Icahn School of Medicine at Mount Sinai

2:30 PM

Networking Coffee Break

3:00 PM

From the Immunogenetic Architecture of Neurodegenerative Diseases to Novel Compounds: Targeting the Myeloid and Microglial Contribution
Philip L. De Jager, MD, PhD, Harvard University and Brigham and Women's Hospital

3:40 PM

Aβ and LPS Mediated Microglial Activation Results in Inhibition of Canonical TGF-β Signaling
Kwame O. Affram, MBChB, Uniformed Services University

4:00 PM

RNA Sequencing Analysis Reveals Potential Mechanisms of Interest to Alzheimer’s Disease
Vishal Sahni, PhD, Eisai Inc.

4:20 PM

Closing Remarks
Sean Pintchovski, PhD, Lundbeck Research USA

4:30 PM

Networking Reception

5:30 PM

Close

Speakers

Organizers

Sean Pintchovski, PhD

Lundbeck Research USA

Dr. Pintchovski earned a BS with Honors from the California Institute of Technology and a PhD in Neuroscience from the University of California, San Francisco. His graduate work at the Gladstone Institute of Neurological Disease/UCSF focused on understanding the regulation of neuronal gene expression underlying memory and cognition. After then completing a postdoctoral fellowship at Elan Pharmaceuticals, where he worked to further elucidate key biochemical processes that contribute to cognitive decline in Alzheimer's disease, Dr. Pintchovski joined the Neuroinflammation Department at Lundbeck Research USA in early 2010. At Lundbeck his efforts have centered on applying a range of powerful techniques, including ex vivo FACS and whole genome expression profiling, to uncover how dysregulation of the innate and adaptive immune systems contributes to the pathogenesis of various neurodegenerative and psychiatric conditions. Dr. Pintchovski is driven by the desire to translate fundamental discoveries into novel therapeutic approaches that will address the medical and social challenges posed by these devastating diseases.

Cynthia Duggan, PhD

The New York Academy of Sciences

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Kwame O. Affram, MBChB

Uniformed Services University

Kwame Ofori Affram graduated with an MBChB degree (MD equivalent) from the University of Ghana Medical School in Accra, Ghana in 2004. He performed his internship in Pediatrics and Surgery at the University affiliated Korle-Bu Teaching Hospital for one year and then continued as a Medical Officer in the same hospital. In 2006 Dr. Affram returned to the University of Ghana Medical School as a teaching assistant in human anatomy and concurrently worked towards an MPhil degree in anatomy which he obtained in 2008. He attended an IBRO School in Teaching Tools for Neuroanatomy in Senegal also in 2008. In 2010 Dr.Affram was accepted into the Graduate Neuroscience Program of the Uniformed Services University, Bethesda, MD and is currently working towards his PhD investigating the regulation of neuroinflammation in the laboratory of Dr. Aviva Symes.

Erik H.W.G.M. Boddeke, PhD

University Medical Center Groningen

Erik Boddeke is professor of Medical Physiology/ Neurophysiology at the department of Neuroscience at the University of Groningen/UMCG, The Netherlands. He finished his PhD thesis at the Department of Pharmacology at the University of Amsterdam. During 1988-1996 he was the laboratory head and group leader Neuro-immunology at Sandoz, in Basle Switzerland. From 1996-1998 he was Vice Head of the Department of Neuro-genetics at Novartis Research in Basle Switzerland. In 1998 he became Professor of Physiology at the Medical Physiology department at the UMC in Groningen (UMCG). As from 1998 till today he is professor of Physiology and Head at the Department of Neuroscience at the UMCG and professor of Medical Biology at the department of Molecular Neuroscience at the faculty of Sciences at the University of Groningen and. He also is director of the Research School BCN. Erik Boddeke’s work is focused on glia, neuroimmunology and ageing and on neural stem cells.

Oleg Butovsky, PhD

Brigham and Women's Hospital and Harvard Medical School

Dr. Butovsky’s major scientific interest is to understand the biology of resident microglia and peripheral inflammatory monocytes in homeostasis and neurodegenerative conditions. During his PhD studies at the Weizmann Institute of Science, he investigated the role of microglial cells in regulating the Ab plaque deposition in AD models, identified subpopulations of microglia and demonstrated how microglia can be both beneficial or detrimental in the context of neurodegeneration. His recently published work has identified a unique microglial signature in both mice and humans and is elucidating the relationship of microglia to CNS diseases including Alzheimer’s disease (AD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). With the new knowledge gained, he hopes to address fundamental questions of microglial biology and apply this knowledge towards the development of novel microglia-targeting therapies. His work was recognized by the Amyotrophic Lateral Sclerosis Association, National Multiple Sclerosis Society and he received the Translational Research Advancing Therapies award and Transformative Research Awards grant from the NIH Director’s Office to provide a new understanding of the function of microglia and macrophages in healthy aging and new therapeutic targets to treat AD, ALS and MS by targeting these unique cell populations.

Philip L. De Jager, MD, PhD

Harvard University and Brigham and Women's Hospital

Philip L. De Jager, MD, PhD is the Steven R. and Kathleen P. Haley Distinguished Chair for the Neurosciences at the Brigham & Women’s Hospital and is an associate professor of neurology at Harvard Medical School. He is the director for basic and translational research at the Institute for the Neurosciences at the Brigham & Women’s Hospital and is an associate member of the Broad Institute of Harvard University and the Massachusetts Institute of Technology. He continues to practice clinical neurology, seeing patients within the Partners Multiple Sclerosis Center that is affiliated with the Brigham & Women’s Hospital and Massachusetts General Hospital in Boston. In 2008, Philip received the prestigious Harry Weaver Neuroscience Scholar Award from the National Multiple Sclerosis Society. His work focuses on understanding the genomic, epigenomic, and neuroimmunologic architecture of neurodegenerative diseases such as multiple sclerosis, Alzheimer’s disease, and aging-related cognitive decline. Philip received his BS (summa cum laude) in molecular biophysics & biochemistry and in French literature from Yale University. He received his PhD in neurogenetics from The Rockefeller University and his MD from Cornell University Medical College. He also completed an MMSc program in clinical investigation at Harvard Medical School and the Massachusetts Institute of Technology. Finally, he completed subspecialty training in neuroimmunology at the Brigham and Women’s Hospital and in human genetics at the Broad Institute.

Joseph El Khoury, MD

Massachusetts General Hospital and Harvard Medical School

Joseph El Khoury is an Infectious Disease physician with an active clinical practice at the Massachusetts General Hospital (MGH) in Boston. After completing postdoctoral studies at Columbia University in New York and at MGH and Harvard Medical School he went on to become a faculty member at Harvard Medical School in 2002. He is the principal investigator for the laboratory for Innate Immunity and Neuroimmunology at the center for Immunology and Inflammatory diseases at MGH. Dr. El Khoury is an expert neuroimmunologist who has dedicated a substantial part of his career to the study of microglia, the innate immune cells of the brain with a focus on the role on these cells in aging and Alzheimer’s disease and is the author of several seminal papers and book chapters in the field. His research is currently supported by several grants from the National Institutes of Health where he also serves as a grant reviewer.

Miriam Merad, MD, PhD

Icahn School of Medicine at Mount Sinai

Miriam Merad, MD, PhD is a Professor of Oncological science, Medicine (Hem/Onc division) and Immunology and a Member of the Immunology Institute and The Tisch Cancer Institute at the Mount Sinai School of Medicine in New York. Dr. Merad obtained her MD at the University of Algiers, Algeria. She did her residency in Hematology and Oncology in Paris, France and obtained her PhD in immunology in collaboration between Stanford University and University of Paris VII. She was recruited to Mount Sinai School of Medicine in 2004 and was promoted to the rank of Associate Professor with Tenure in 2007 and to Full Professor in 2010 and obtained an endowed Professorship in 2014. In 2010 Dr. Merad became the program leader of the Cancer immunology immunotherapy group at The Tisch Cancer Institute and the director of the Human Immunomonitoring center. Dr. Merad also serves as the Associate Director for the MD PhD program at Mount Sinai Medical School. Dr. Merad’s laboratory studies the mechanisms that regulate the development and function of the mononuclear phagocyte lineage including dendritic cells and macrophages. Her laboratory has extensively studied the mechanisms that control dendritic cells and macrophage homeostasis in different tissues including the brain. Dr. Merad has also made seminal discoveries in microglial biology revealing their embryonic origin and their local maintenance in situ. Dr. Merad’s belongs to the Immgen consortia to help decipher the transcriptional regulation of the tissue dendritic cell and macrophage lineage. Currently, one of the major goals of her laboratory is to identify the contribution of phagocytes to disease outcome including cancer and microbial immunity. Dr. Merad has authored more than 100 primary papers and reviews in high profile journal and obtained extensive NIH funding for her studies on dendritic cells and macrophage biology in mice and humans.

Michael C. Oldham, PhD

University of California, San Francisco

Michael C. Oldham, PhD is a neuroscientist and UCSF Sandler Fellow in The Broad Center of Regeneration Medicine and Stem Cell Research at the University of California, San Francisco. Dr. Oldham's lab studies the organization of the human brain transcriptome as a window unto neurobiological cellular complexity and identity in health and disease. As a graduate student in Dan Geschwind's laboratory at UCLA, he performed the first gene coexpression analysis of microarray data from human brain samples. This work demonstrated that cell type-specific information can be recovered from brain tissue without isolating homogeneous populations of cells and provided an initial description of the transcriptional programs that distinguish the major cell classes of the human brain. During a brief postdoc in Steve Horvath's laboratory at UCLA, he developed software to streamline processing of large gene expression datasets. After only a few months in this position, Dr. Oldham was unanimously selected as the 17th UCSF Sandler Fellow and provided with funding and space to start his own lab. As a Principal Investigator, Dr. Oldham continues to develop and apply new methods to refine the cellular and molecular taxonomy of the nervous system in health and disease on the basis of gene expression.

Vishal Sahni, PhD

Eisai Inc.

Dr. Vishal Sahni is a Senior Scientist in Eisai Inc.’s Translational Neurogenomics Group, located in Andover, Massachusetts. His work focuses on functional neurogenomics analyses to catalyse drug discovery from human genetics. Prior to relocating to the US, he was leading CNS discovery projects from Target validation up to Candidate Selection at Eisai Ltd, Hatfield, UK. He holds a PhD in Developmental Neurobiology from University College London, where he studied the generation and transdifferentiation of glial-biased stem cells from peripheral nerves. He also holds a Masters degree from Imperial College London and a BSc degree from King’s College London, both focused on developmental and clinical Neuroscience.

Bin Zhang, PhD

Icahn School of Medicine at Mount Sinai

Dr. Bin Zhang is an associate professor of the Department of Genetics and Genomic Sciences and a member of the Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA. Prior to his appointment at Mount Sinai, he was a Principal Scientist and Group Leader of Sage Bionetworks, a non-profit research organization started in 2009 that grew out of a decade of intense well-funded work at Rosetta Inpharmatics, a wholly owned subsidiary of Merck & Co. Before he joined Sage, he worked at Merck & Co. first as a senior research scientist from and then as a Research Fellow. Prior to joining Merck & Co., he was a post-doctoral fellow and then a Research Faculty and Senior Biostatistician at David Geffen Medical School of University of California at Los Angeles. He holds a Ph.D. and a master degree in Computer Science from the State University of New York at Buffalo, a master degree in electronic engineering from Tsinghua University, Beijing, China, and a bachelor's degree in electrical engineering from Tongji University, Shanghai, China. His expertise lies in bioinformatics and computational biology, image processing, pattern recognition and data mining. He has developed and significantly contributed to several influential gene network inference algorithms which have been extensively used to identify pathways and gene targets involved in a variety of diseases such as cancer, atherosclerosis, Alzheimer's, obesity and diabetes etc. He has published 79 peer-reviewed papers including 8 papers in Nature, Nature Genetics, Cell and PNAS. As of October 2013, his publications have been cited 4903 times, according to Google Scholar.

Sponsors

For sponsorship opportunities please contact Perri Wisotsky at pwisotsky@nyas.org or 212.298.8642.

Academy Friend

Lundbeck Research USA, Inc.

Promotional Partners

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American Federation for Aging Research

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The Brain Dysfunction Discussion Group is proudly supported by

  • Acorda Therapeutics
  • Pfizer

Mission Partner support for the Frontiers of Science program provided by   Pfizer

Abstracts

Transcriptional Signatures of Microglia in Normal and Diseased Human Brain
Michael C. Oldham, PhD, University of California, San Francisco

Microglia have emerged as a focal point for efforts to unravel the pathogenesis of Alzheimer's disease (AD) and other neurological disorders. To elucidate the potential contributions of microglia to AD, we must first cultivate a better understanding of microglial phenotypes in the normal adult human brain. Toward this end, we are focused on characterizing the transcriptional profile of microglia (and other cell types) in non-pathological adult human brain samples. Because the human brain is comprised of many different cell types, it is widely assumed that identifying the cellular source(s) of specific transcripts is impossible without analyzing purified cellular populations or individual cells; however, this assumption is invalid. By analyzing genome-wide gene coexpression relationships in transcriptomic data generated from heterogeneous tissue samples, it is possible to isolate transcriptional signatures of distinct cell types in silico without performing physical isolation or purification of individual cell types. This ability follows inevitably from two simple ideas: i) different cell types express different genes, and ii) the relative abundance of each cell type will vary among heterogeneous tissue samples. Using this strategy, we have observed transcriptional signatures of microglia in a large collection of gene expression datasets representing nearly seven thousand adult human brain samples. These signatures are extremely robust and predict gene expression specificity in microglia under non-pathological conditions. As such, they provide a multivariate and precise quantitative framework for examining perturbations in a broad range of microglial phenotypes that may contribute to AD and other neurological disorders.
 

Multiscale Gene Network Modeling of Late-Onset Alzheimer’s Disease
Bin Zhang, PhD, Icahn School of Medicine at Mount Sinai

Despite decades of intensive research, the causal chains of mechanisms underlying Late-Onset Alzheimer’s Disease (LOAD) remains elusive. New approaches need be developed to identify the causal genes and pathways in LOAD. In this study, we conducted an integrative multiscale network-based analysis of DNA and mRNA data in 1647 post-mortem tissues from multiple brain regions of subjects diagnosed with LOAD and normal disease-free controls. A massive remodeling of network structures in LOAD was observed and quantified to objectively rank order subnetworks for relevance to LOAD pathology. Gene causal networks were further constructed to identify key drivers and develop mechanisms. This multiscale network-based analysis reveals a subnetwork involved in immune response as the top ranking with respect to LOAD pathology. We further experimentally validated a predicted key driver of this immune response subnetwork by demonstrating its involvement in amyloid-β turnover and neuronal damage as well as its capability of regulating its downstream targets.
 

Identification of a Unique Molecular and Functional Microglia Signature in Health and Disease
Oleg Butovsky, PhD, Brigham and Women's Hospital and Harvard Medical School

Microglia are resident macrophages of the central nervous system (CNS) that participate both in normal CNS function and disease. We identified a unique molecular and functional homeostatic signature in microglia. Based on this signature, we generated novel microglial surface specific antibodies and identified novel targets in resident microglia that can serve as therapeutic targets. We also identified unique patterns of microglia dysfunction associated with CNS disease in animal models of EAE, ALS and AD. We found that the homeostatic microglial signature is dependent on TGFb signaling. In mouse models of MS, ALS and AD, microglia acquire a cytotoxic phenotype mediated by intrinsic activation of the APOE pathway which suppresses the microglia homeostatic molecular properties and leads to uncontrolled chronic inflammation. Treatments aimed at targeting microglia by suppressing the APOE pathway result in activation of both the TGFb pathway and TAM system (Tyro3, Axl and Mertk), which abrogates the inflammatory microglial phenotype and restores microglial homeostatic properties. In summary, we have identified the APOE-TGFb axis as a critical common regulatory pathway in microglia. This pathway is dysregulated in both inflammatory and degenerative diseases of the CNS.
 

Parsing Microglial Phenotypes by Comparing Chronic and Acute Inflammatory Conditions
Erik H.W.G.M. Boddeke, PhD, University Medical Center Groningen

Microglia are yolk sac-derived myeloid cells that constitute an autonomous local population of tissue macrophages in the central nervous system. Whereas resting microglia play a role in tissue surveillance, upon loss of homeostasis, microglia change to an activated phenotype. A complex variety of activated microglia phenotypes under a range of pathological conditions has been described. In order to provide an unambiguous description of activated microglia phenotypes, we have studied the expression profile of microglia in mouse models for acute microglia activation, microglia priming and -tolerance. In various mouse models for aging and neurodegenerative disease a highly conserved gene module was identified in primed microglia that differed significantly from acutely activated microglia. This primed microglia gene module was associated with GO terms for immune response, cell stress, phagosome and metabolism. Microglia from LPS-tolerized mice were associated with only minor changes in gene expression. Characterization of the epigenetic profile of tolerant microglia showed a significant enrichment for repressive histone modifications in the promoter region of proinflammatory cytokines and indicated a requirement of NF-kB subunit RelB for microglia tolerance. Clearly transcriptome- and epigenetic profiling provides useful fingerprints for microglia phenotype description.
 

RNA-Seq Reveals a Dynamic Microglial Sensome
Joseph El Khoury, MD, Massachusetts General Hospital and Harvard Medical School

Maintaining the Microglia Status Quo: CNS Signals that Determine Microglia Homeostasis
Miriam Merad, MD, PhD, Icahn School of Medicine at Mount Sinai

Microglia refer to the tissue-resident macrophages that populate the brain. Microglia are the only cells of hematopoietic origin that reside in the steady state brain and have been shown to play a key role in brain immunity and homeostasis. Our group has been exploring the mechanisms that control microglia development and function for many years. Here I will discuss our studies showing that microglia seed the brain very early during development and are maintained locally in the adult brain through longevity or self-renewal. Microglia survival and function is therefore dependent on local tissue factors, which we believe also contribute to the maintenance of brain tissue integrity. I will discuss more recent results on identifying the brain factors that contribute to the maintenance of microglia in the adult brain.
 

From the Immunogenetic Architecture of Neurodegenerative Diseases to Novel Compounds: Targeting the Myeloid and Microglial Contribution
Philip L. De Jager, MD, PhD, Harvard University and Brigham and Women's Hospital

We will review recent results of systematic evaluations of the peripheral immune system that demonstrate an enrichment of functional consequences of genetic variants associated with neurodegenerative diseases in innate immune cells such as monocytes relative to the adaptive immune system represented by T cells. This important result focuses our attention on understanding the pathways found in innate immune cells that have been implicated in Alzheimer’s disease (AD): certain functions of resident microglial cells and infiltrating macrophages are targeted by susceptibility variants. These susceptibility networks are emerging from a unique dataset of over 500 subjects with RNA sequence data from their dorsolateral prefrontal cortex, where we can relate specific networks to post-mortem neuropathologic indices and ante-mortem performance on neuropsychologic tests as well as clinical diagnoses. Further, we are beginning to map how these susceptibility variants interact with one another and to identify key nodes in the AD susceptibility network. Using human in vitro models of primary cells, we are validating these network models and translating them to identify compounds that are blocking the effect of genetic variants, including CD33.
 

Aβ and LPS Mediated Microglial Activation Results in Inhibition of Canonical TGF- β Signaling
Kwame O. Affram, MBChB, Uniformed Services University

Chronic neuroinflammation mediated by persistent microglial activation is associated with neurodegeneration in Alzheimer’s disease. TGF-β1 is an anti-inflammatory cytokine that plays a major role in maintaining microglial quiescence and promoting the alternative activation state. Our previous study demonstrated that TGF-β1 signaling is suppressed in LPS-activated microglia thereby predisposing microglia to prolonged activation. We hypothesized that Aβ, a pathogenic peptide in Alzheimer’s disease, can also alter TGF-β signaling in microglia thereby prolonging activation of these cells. Similar to that observed in LPS-treated microglia, we showed that Aβ treatment resulted in down regulation of the TGF-β receptor, TβR1, in rat primary microglia. Further, TGF-β1-mediated gene transcription was significantly reduced in Aβ-treated rat primary microglia. Additional experiments with LPS demonstrated that down regulation of TβR1 mRNA was prevented by inhibition of the NFkb pathway but not the MAP Kinase pathway. We also observed induction of negative regulators of TGF-β1 signaling in LPS-activated microglia including BAMBI and SnoN. Surprisingly, Smad7, which is commonly induced in other cell types, in an NFkb-dependent manner to negatively regulate TGF-β signaling, was not upregulated in LPS-activated microglia. Finally we showed that Aβ treatment reduced TGF-β1-mediated microglial cell death similar to that previously shown with LPS treatment. Thus, these data indicate that suppression of TGF-β signaling may be a common mechanism for microglia activators to prolong activation of microglia. Identifying ways to restore TGF-β1 signaling in activated microglia may yield novel strategies for reducing chronic neuroinflammation and ameliorating the neurodegeneration in Alzheimer’s disease.
 

RNA Sequencing Analysis Reveals Potential Mechanisms of Interest to Alzheimer’s Disease
Vishal Sahni, PhD, Eisai Inc.

Neuroinflammation is an area of renewed interest in the neurological disease therapeutic area in light of recent findings from large-scale genetic association studies. In order to prosecute neuroinflammation-related drug targets, it is critical to elucidate the biological role of genes of interest utilizing a repertoire of wet-lab experiments and to be supported by human biology gained from analysis of patient samples. To this end, we carried out a RNA sequencing study of post-mortem hippocampal tissue of Alzheimer’s disease patients at various disease stages (n=50) and age-matched non-Alzheimer’s disease subjects (n=21). We describe a preliminary analysis of our RNA sequencing data with a focus on Quality Control variables, such as inter-centre variability in gene expression profiles. In addition, we also outline our preliminary results from a pathway analysis algorithm which points towards enrichment in differentially regulated genes associated with innate and adaptive immunity.
 

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