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ANK1 Is Up-Regulated in Laser Captured Microglia in Alzheimer’S Brain; the Importance of Addressing Cellular Heterogeneity

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ANK1 Is Up-Regulated in Laser Captured Microglia in Alzheimer’S Brain; the Importance of Addressing Cellular Heterogeneity View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Open Research Exeter RESEARCH ARTICLE ANK1 is up-regulated in laser captured microglia in Alzheimer's brain; the importance of addressing cellular heterogeneity Diego Mastroeni1,2*, Shobana Sekar3, Jennifer Nolz1, Elaine Delvaux1, Katie Lunnon4, Jonathan Mill4,5, Winnie S. Liang3, Paul D. Coleman1,2 1 Biodesign, ASU-Banner Biodesign Neurodegenerative Disease Research Center, and School of Life Sciences, Arizona State University, Tempe, AZ, United States of America, 2 Banner Sun Health Research a1111111111 Institute, 10515 West Santa Fe Drive, Sun City, AZ, United States of America, 3 Translational Genomics a1111111111 Institute, 445 North Fifth Street, Phoenix, AZ, United States of America, 4 University of Exeter Medical a1111111111 School, RILD, University of Exeter, Devon, United Kingdom, 5 Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London, United Kingdom a1111111111 a1111111111 * [email protected] Abstract OPEN ACCESS Recent epigenetic association studies have identified a new gene, ANK1, in the pathogene- Citation: Mastroeni D, Sekar S, Nolz J, Delvaux E, sis of Alzheimer's disease (AD). Although strong associations were observed, brain homog- Lunnon K, Mill J, et al. (2017) ANK1 is up- regulated in laser captured microglia in Alzheimer's enates were used to generate the data, introducing complications because of the range of brain; the importance of addressing cellular cell types analyzed. In order to address the issue of cellular heterogeneity in homogenate heterogeneity. PLoS ONE 12(7): e0177814. https:// samples we isolated microglial, astrocytes and neurons by laser capture microdissection doi.org/10.1371/journal.pone.0177814 from CA1 of hippocampus in the same individuals with a clinical and pathological diagnosis Editor: Stephen D. Ginsberg, Nathan S Kline of AD and matched control cases. Using this unique RNAseq data set, we show that in the Institute, UNITED STATES hippocampus, ANK1 is significantly (p<0.0001) up-regulated 4-fold in AD microglia, but not Received: October 13, 2016 in neurons or astrocytes from the same individuals. These data provide evidence that micro- Accepted: May 3, 2017 glia are the source of ANK1 differential expression previously identified in homogenate sam- Published: July 12, 2017 ples in AD. Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Introduction The work is made available under the Creative Alzheimer's disease (AD) is a multi-factorial neurological disorder classically characterized by Commons CC0 public domain dedication. amyloid plaques[1] and neurofibrillary tangles[2]. AD also features many signs of chronic Data Availability Statement: All relevant data are inflammation[3, 4]. Microglia, resident immune cells within the central nervous system, are within the paper and its Supporting Information key regulators of the inflammatory cascade[5], which has been proposed as an early event in files. This is the first time the laser capture data has been shared. The supporting information contains AD[6, 7]. It has been known for decades that microglia have the ability to release neuro-toxic the gene list details including the ensemble inflammatory factors, which have prompted hundreds of studies to address a causal mecha- accession numbers/gene names. Homogenate nism[8]. Although may genetic association studies have identified potential glial-associated samples have been used in a previous microarray alterations (e.g. TREM2) [9], none have been absolute in predicting disease. Recent studies study (Bechtold et al., 2008) for which data have have reached beyond genetic variation, but instead looked towards epigenetic changes as a been deposited in the Gene Expression Omnibus database (www.ncbi.nlm.nih.gov/geo) accession mechanism by which environment can interact with genome. number GSE11882. The complete dataset can As such, recent epigenetic-wide association studies (EWAS) have identified a class of genes found at the National Institute on Aging Genetics of associated with AD risk. Ankyrin repeat domain-containing proteins are plasma bound PLOS ONE | https://doi.org/10.1371/journal.pone.0177814 July 12, 2017 1 / 11 ANK1 is up-regulated in laser captured microglia in Alzheimer's brain Alzheimer's Disease data storage site (https://www. membrane proteins, which modulate interactions between cytoskeletal and membrane pro- niagads.org/) under accession number NG00057. teins[10]. A specific ankyrin repeat domain-containing protein, ANK1, has been a source of Funding: This work was supported by New great interest in the field of AD[11±13] and type 2 diabetes[14, 15], a recognized risk factor for Investigator Research Grant-Alzheimer's AD[16]. Two independent EWAS have identified methylation changes in the ANK1 gene that Association NIRG-15-321390 and Arizona are associated with AD[11, 12]. These studies indicate that epigenetic mechanisms (e.g. DNA Department of Health Services ADHS16-104646 methylation) and the rise of age-dependent inflammatory conditions are major risk factors for FY2015-16 to D.M. The funders had no role in study design, data collection and analysis, decision AD, and ANK1 may be the link between the two[12]. However, these studies which draw atten- to publish, or preparation of the manuscript. tion to ANK1 as a potentially critical molecule in the pathophysiology of AD were conducted on homogenates brain samples, which leaves unresolved the identity of the cells impacted by Competing interests: The authors have declared that no competing interests exist. DNA hypermethylation in AD. Here, we provide evidence that microglia are the source of ANK1 differential expression in the AD brain. Methods Ethics statement Written informed consent for autopsy was obtained in compliance with institutional guide- lines of Banner Sun Health Research Institute. Banner Sun Health Research Institute Review Board approved this study including recruitment, enrollment, and autopsy procedures. Indi- vidual person(s) and their respective next-of-kin consented to brain autopsy for the purpose of research analysis as participants in the Banner Sun Health Research Institute brain and body donation program. The human brain tissue used in this manuscript was from routine existing autopsies, which fully qualifies for 4C exemption by NIH guidelines. In addition, samples were analyzed anonymously (e.g. sample numbers) throughout the experimental process. Laser capture microdissection of microglia and RNA sequencing Tissue collection. Frozen unfixed tissue containing CA1 of hippocampus were collected at Sun Health Research Institute (Alzheimer's Disease Centers) from clinically and neuro- pathologically classified late-onset AD-afflicted individuals with a mean age of 74.6 ± 6.8 years; healthy elderly controls with a mean age of 73.6 ± 6 years; and Parkinson's disease cases with a mean age of 74.6 ± 15.6 years. Detailed sample information, including post mortem interval (PMI) can be found in Table 1. Immunohistochemistry for laser capture. Frozen brain tissue sections (10μm) were mounted onto PEN slides and fixed in ice cold acetone/ethanol for 10 min on ice. Sections were washed in ice cold 1X Phosphate buffered saline (PBS), blocked in 1% hydrogen peroxide for 2 minutes, followed by 3 quick submersions in ice cold 1X PBS. Sections were then placed in 1:500 dilution of primary antibody in 1X PBS supplemented with 50U RNAseOUT (Invitro- gen) for 10 minutes at room temperature. After the incubation, sections were washed three times in 1X PBS and incubated in avidin(1:300)-biotin(1:300) complex (Vector) in 1X PBS for 10 minutes at room temperature (RT). Sections were washed three times in 50mM Tris buffer and immersed in 3.3'-diaminobenzidine (DAB) solution (9.3 ml 50mM Tris; 200 μl DAB (5mg/ml); 500 μl saturated nickel; and 4 μl of 1% H202) for 5 minutes, followed by two quick rinses in 50mM Tris to stop the reaction. Laser capture of LN3-positive microglia. LN3 antibody reacts with MHCII microglia. These microglia are said to be antigen presenting (e.g. activated, M1 phase, but not phagocytic M2). Immediately after detection of LN3-immunoreactivity, sections were dipped in 100% ethanol and loaded onto a Leica AS-LMD laser capture microscope. After objective calibration, 600 LN3-positive cells were captured using 20X magnification. Individual microglial cells were cut and dropped into an inverted microcentrifuge cap containing 50μl buffer RLT (RNeasy PLOS ONE | https://doi.org/10.1371/journal.pone.0177814 July 12, 2017 2 / 11 ANK1 is up-regulated in laser captured microglia in Alzheimer's brain Table 1. Clinical and pathological patient demographics. Gender Clinical and Pathological Diagnosis Expired Age PMI APOE Braak RIN Values Whole Tissue NFT Stage Male ND 93 3 3/3 I 6.9 Male ND 73 2.5 2/3 II 7 Male ND 89 5.5 3/3 II 7.8 Male ND 79 3 3/3 II 7 Male ND 53 3.66 3/3 I 7.1 Male ND 61 2.33 3/3 I 7 Male AD 75 2 3/4 V 7.3 Male AD 70 2.33 3/4 V 6.7 Male AD 76 4 4/4 V 7.1 Male AD 64 2.33 3/3 VI 7.2 Male AD 82 2.95 3/3 V 7.3 Male AD 75 3.83 3/4 V 7.1 Male PD 69 2.25 3/4 II 7 Male PD 72 3.5 2/3 II 7.2 Male PD 70 2.33 3/3 II 7.8 Male PD 69 3.37 3/3 II 7.5 Male PD 78 2.75 3/3 II 7.1 Male PD 86 3 3/3 III 6.9 https://doi.org/10.1371/journal.pone.0177814.t001 Micro KitÐQiagen) and 1% β-Mercaptoethanol. Detailed schematic of laser capture can be seen in (S1 Fig).
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