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Central role for PICALM in amyloid-ß blood-brain barrier transcytosis and clearance.
Zhao, Zhen; Sagare, Abhay P; Ma, Qingyi; Halliday, Matthew R; Kong, Pan; Kisler, Kassandra; Winkler, Ethan A; Ramanathan, Anita; Kanekiyo, Takahisa; Bu, Guojun; Owens, Nelly Chuqui; Rege, Sanket V; Si, Gabriel; Ahuja, Ashim; Zhu, Donghui; Miller, Carol A; Schneider, Julie A; Maeda, Manami; Maeda, Takahiro; Sugawara, Tohru; Ichida, Justin K; Zlokovic, Berislav V.
Afiliación
  • Zhao Z; Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • Sagare AP; Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • Ma Q; Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • Halliday MR; Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • Kong P; Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • Kisler K; Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • Winkler EA; 1] Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. [2] Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
  • Ramanathan A; Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • Kanekiyo T; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Bu G; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Owens NC; Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • Rege SV; Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • Si G; Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • Ahuja A; Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • Zhu D; Department of Chemical, Biological and Bioengineering, North Carolina Agricultural and Technical State University, Greensboro, North Carolina, USA.
  • Miller CA; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • Schneider JA; Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
  • Maeda M; 1] Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute of the City of Hope, Duarte, California, USA. [2] Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Maeda T; 1] Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute of the City of Hope, Duarte, California, USA. [2] Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Sugawara T; 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, Los Angeles, California, USA.
  • Ichida JK; 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, Los Angeles, California, USA.
  • Zlokovic BV; Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Nat Neurosci ; 18(7): 978-87, 2015 Jul.
Article en En | MEDLINE | ID: mdl-26005850
ABSTRACT
PICALM is a highly validated genetic risk factor for Alzheimer's disease (AD). We found that reduced expression of PICALM in AD and murine brain endothelium correlated with amyloid-ß (Aß) pathology and cognitive impairment. Moreover, Picalm deficiency diminished Aß clearance across the murine blood-brain barrier (BBB) and accelerated Aß pathology in a manner that was reversible by endothelial PICALM re-expression. Using human brain endothelial monolayers, we found that PICALM regulated PICALM/clathrin-dependent internalization of Aß bound to the low density lipoprotein receptor related protein-1, a key Aß clearance receptor, and guided Aß trafficking to Rab5 and Rab11, leading to Aß endothelial transcytosis and clearance. PICALM levels and Aß clearance were reduced in AD-derived endothelial monolayers, which was reversible by adenoviral-mediated PICALM transfer. Inducible pluripotent stem cell-derived human endothelial cells carrying the rs3851179 protective allele exhibited higher PICALM levels and enhanced Aß clearance. Thus, PICALM regulates Aß BBB transcytosis and clearance, which has implications for Aß brain homeostasis and clearance therapy.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Barrera Hematoencefálica / Corteza Cerebral / Péptidos beta-Amiloides / Proteínas de Ensamble de Clatrina Monoméricas / Enfermedad de Alzheimer Tipo de estudio: Risk_factors_studies Idioma: En Revista: Nat Neurosci Asunto de la revista: NEUROLOGIA Año: 2015 Tipo del documento: Article
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Barrera Hematoencefálica / Corteza Cerebral / Péptidos beta-Amiloides / Proteínas de Ensamble de Clatrina Monoméricas / Enfermedad de Alzheimer Tipo de estudio: Risk_factors_studies Idioma: En Revista: Nat Neurosci Asunto de la revista: NEUROLOGIA Año: 2015 Tipo del documento: Article