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      Innate immunity protein IFITM3 modulates γ-secretase in Alzheimer disease

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          Abstract

          Innate immunity is associated with Alzheimer disease (AD) 1 , however, the influence of immune activation on Aβ production is unknown 2, 3 . Here, we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, establishing a mechanism by which inflammation impacts Aβ generation. Inflammatory cytokines in neurons and astrocytes induce IFITM3 which binds to γ-secretase and upregulates its activity for Aβ production. IFITM3 expression is increased with aging and familial Alzheimer disease’s genes in mouse models. Furthermore, IFITM3 knock out reduces γ-secretase activity and the formation of amyloid plaques in 5XFAD mice. IFITM3 protein is upregulated in a subset of late onset AD (LOAD) patients that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in LOAD. These findings reveal an unprecedented mechanism in which γ-secretase is modulated by IFITM3 by neuroinflammation and increases risks for AD.

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          Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans.

          (2015)
          Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysis of RNA sequencing data from 1641 samples across 43 tissues from 175 individuals, generated as part of the pilot phase of the Genotype-Tissue Expression (GTEx) project. We describe the landscape of gene expression across tissues, catalog thousands of tissue-specific and shared regulatory expression quantitative trait loci (eQTL) variants, describe complex network relationships, and identify signals from genome-wide association studies explained by eQTLs. These findings provide a systematic understanding of the cellular and biological consequences of human genetic variation and of the heterogeneity of such effects among a diverse set of human tissues. Copyright © 2015, American Association for the Advancement of Science.
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            Linear models and empirical bayes methods for assessing differential expression in microarray experiments.

            Gordon K. Smyth (2004)
            The problem of identifying differentially expressed genes in designed microarray experiments is considered. Lonnstedt and Speed (2002) derived an expression for the posterior odds of differential expression in a replicated two-color experiment using a simple hierarchical parametric model. The purpose of this paper is to develop the hierarchical model of Lonnstedt and Speed (2002) into a practical approach for general microarray experiments with arbitrary numbers of treatments and RNA samples. The model is reset in the context of general linear models with arbitrary coefficients and contrasts of interest. The approach applies equally well to both single channel and two color microarray experiments. Consistent, closed form estimators are derived for the hyperparameters in the model. The estimators proposed have robust behavior even for small numbers of arrays and allow for incomplete data arising from spot filtering or spot quality weights. The posterior odds statistic is reformulated in terms of a moderated t-statistic in which posterior residual standard deviations are used in place of ordinary standard deviations. The empirical Bayes approach is equivalent to shrinkage of the estimated sample variances towards a pooled estimate, resulting in far more stable inference when the number of arrays is small. The use of moderated t-statistics has the advantage over the posterior odds that the number of hyperparameters which need to estimated is reduced; in particular, knowledge of the non-null prior for the fold changes are not required. The moderated t-statistic is shown to follow a t-distribution with augmented degrees of freedom. The moderated t inferential approach extends to accommodate tests of composite null hypotheses through the use of moderated F-statistics. The performance of the methods is demonstrated in a simulation study. Results are presented for two publicly available data sets.
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              Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation.

              Holly D. Oakley, Sarah L Cole, Sreemathi Logan … (2006)
              Mutations in the genes for amyloid precursor protein (APP) and presenilins (PS1, PS2) increase production of beta-amyloid 42 (Abeta42) and cause familial Alzheimer's disease (FAD). Transgenic mice that express FAD mutant APP and PS1 overproduce Abeta42 and exhibit amyloid plaque pathology similar to that found in AD, but most transgenic models develop plaques slowly. To accelerate plaque development and investigate the effects of very high cerebral Abeta42 levels, we generated APP/PS1 double transgenic mice that coexpress five FAD mutations (5XFAD mice) and additively increase Abeta42 production. 5XFAD mice generate Abeta42 almost exclusively and rapidly accumulate massive cerebral Abeta42 levels. Amyloid deposition (and gliosis) begins at 2 months and reaches a very large burden, especially in subiculum and deep cortical layers. Intraneuronal Abeta42 accumulates in 5XFAD brain starting at 1.5 months of age (before plaques form), is aggregated (as determined by thioflavin S staining), and occurs within neuron soma and neurites. Some amyloid deposits originate within morphologically abnormal neuron soma that contain intraneuronal Abeta. Synaptic markers synaptophysin, syntaxin, and postsynaptic density-95 decrease with age in 5XFAD brain, and large pyramidal neurons in cortical layer 5 and subiculum are lost. In addition, levels of the activation subunit of cyclin-dependent kinase 5, p25, are elevated significantly at 9 months in 5XFAD brain, although an upward trend is observed by 3 months of age, before significant neurodegeneration or neuron loss. Finally, 5XFAD mice have impaired memory in the Y-maze. Thus, 5XFAD mice rapidly recapitulate major features of AD amyloid pathology and may be useful models of intraneuronal Abeta42-induced neurodegeneration and amyloid plaque formation.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 0410462
                Journal ID (pubmed-jr-id): 6011
                Journal ID (nlm-ta): Nature
                Journal ID (iso-abbrev): Nature
                Title: Nature
                ISSN (Print): 0028-0836
                ISSN (Electronic): 1476-4687
                Publication date Nihms-submitted: 8 February 2021
                Publication date (Electronic): 02 September 2020
                Publication date (Print): October 2020
                Publication date PMC-release: 02 March 2021
                Volume: 586
                Issue: 7831
                Pages: 735-740
                Affiliations
                [1 ]Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
                [2 ]Program of Neurosciences, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
                [3 ]Program of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
                [4 ]Ronald M. Loeb Center for Alzheimer’s Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
                [5 ]Department of Genetics and Genomic Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
                [6 ]Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY, USA.
                [7 ]Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
                [8 ]Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
                [9 ]Pfizer Worldwide Research and Development, Cambridge, MA, USA.
                Author notes
                [ξ]

                Equal Contributions

                [€]

                Deceased

                Author Contributions: J.-Y.H. and Y.-M.L. conceived the study. J.-Y.H., G.R.F. Y.-M.L. planned and J.-Y.H., G.R.F., X.W. performed most of the experiments and J.-Y.H., G.R.F., Y.-M.L. analyzed the data. X.W. and C.C. performed proteomics study. S.J.P. and E.W. cloned the constructs and S.J.P. expressed a recombinant substrate protein. E.W. performed a photolabeling study in primary neurons and Notch AlphaLISA assay in KO cells. M.B. performed IF. T.L. perfused mouse brains and T.L., Y.Z. and Y. K. helped primary neuronal culture. P.N. synthesized compounds. J.C.W. assisted gene expression studies and analyzed the large human brain dataset. J. T. cultured human iPSC-derived neurons and astrocytes and performed IF. L.G., A. M., C.M., X.Z., M.W. and B.Z. analyzed gene expression in a large human brain dataset. Y. S. performed qPCR in mouse hippocampal cells and analyzed the data. A.E.R. and B.T.E. performed SNP genotyping and analyzed the data. K.R.S. and R.V. coordinated and provided 5XFAD Tg tissue samples. I.T., R.A.R. and E.M. coordinated and provided the collection of human brain samples. G.R.F. summarized findings in illustration. J.-Y.H., J.C.W., R.V., B.Z., D.S.J., E.M., P.G., A.G. and Y.–M.L. analyzed the data. J.-Y.H. wrote the initial draft of the manuscript and, J.-Y.H., G.R.F. and Y.–M.L. revised the manuscript. All authors discussed and commented on the manuscript.

                [* ] Correspondence to: liy2@ 123456mskcc.org
                Article
                Manuscript ID: NIHMS1599391
                DOI: 10.1038/s41586-020-2681-2
                PMC ID: 7919141
                PubMed ID: 32879487
                SO-VID: a865f2aa-5c34-4f35-9a55-b7e1eea8e76e
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