Blog
About

28
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Central role for PICALM in amyloid–β blood–brain barrier transcytosis and clearance

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          PICALM is highly validated genetic risk factor for Alzheimer’s disease (AD). Here, we report that PICALM reductions in AD and murine brain endothelium correlate with amyloid–β (Aβ) pathology and cognitive impairment. Moreover, Picalm deficiency diminishes Aβ clearance across the murine blood–brain barrier (BBB) and accelerates Aβ pathology that is reversible by endothelial PICALM re–expression. Using human brain endothelial monolayer, we show that PICALM regulates PICALM/clathrin–dependent internalization of Aβ bound to the low density lipoprotein receptor related protein–1, a key Aβ clearance receptor, and guides Aβ trafficking to Rab5 and Rab11 leading to Aβ endothelial transcytosis and clearance. PICALM levels and Aβ clearance were reduced in AD–derived endothelial monolayers, which was reversible by adenoviral–mediated PICALM transfer. iPSC–derived human endothelial cells carrying the rs3851179 protective allele exhibited higher PICALM levels and enhanced Aβ clearance. Thus, PICALM regulates Aβ BBB transcytosis and clearance that has implications for Aβ brain homeostasis and clearance therapy.

          Related collections

          Most cited references 57

          • Record: found
          • Abstract: found
          • Article: not found

          RNA-guided human genome engineering via Cas9.

           P. Mali,  L. YANG,  K. Esvelt (2013)
          Bacteria and archaea have evolved adaptive immune defenses, termed clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems, that use short RNA to direct degradation of foreign nucleic acids. Here, we engineer the type II bacterial CRISPR system to function with custom guide RNA (gRNA) in human cells. For the endogenous AAVS1 locus, we obtained targeting rates of 10 to 25% in 293T cells, 13 to 8% in K562 cells, and 2 to 4% in induced pluripotent stem cells. We show that this process relies on CRISPR components; is sequence-specific; and, upon simultaneous introduction of multiple gRNAs, can effect multiplex editing of target loci. We also compute a genome-wide resource of ~190 K unique gRNAs targeting ~40.5% of human exons. Our results establish an RNA-guided editing tool for facile, robust, and multiplexable human genome engineering.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.

             D. Selkoe,  John Hardy (2002)
            It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid beta-peptide (Abeta) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Abeta in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Abeta production and Abeta clearance.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.

              Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
                Bookmark

                Author and article information

                Journal
                9809671
                21092
                Nat Neurosci
                Nat. Neurosci.
                Nature neuroscience
                1097-6256
                1546-1726
                6 May 2015
                25 May 2015
                July 2015
                01 January 2016
                : 18
                : 7
                : 978-987
                Affiliations
                [1 ]Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
                [2 ]Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
                [3 ]Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
                [4 ]Department of Chemical, Biological and Bio–Engineering, North Carolina Agricultural and Technical State University, Greensboro, NC 27411, USA
                [5 ]Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
                [6 ]Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA
                [7 ]Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
                [8 ]Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
                [9 ]Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, 1425 San Pablo Street, BCC 307, Los Angeles, CA 90089, USA
                Author notes
                [] Address correspondence: Berislav V. Zlokovic, M.D., Ph.D. Zilkha Neurogenetic Institute, Room: 101, 1501 San Pablo Street, Los Angeles, CA 90089, Phone: 323.442.2722 / Fax: 323.666.2184, zlokovic@ 123456usc.edu
                [10]

                These authors contributed equally to this work.

                Article
                NIHMS684788
                10.1038/nn.4025
                4482781
                26005850
                Categories
                Article

                Neurosciences

                Comments

                Comment on this article