title: Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance.
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-β (Aβ) pathology and cognitive impairment. Moreover, Picalm deficiency diminished Aβ clearance across the murine blood-brain barrier (BBB) and accelerated Aβ 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 Aβ bound to the low density lipoprotein receptor related protein-1, a key Aβ clearance receptor, and guided 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. Inducible pluripotent stem cell-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, which has implications for Aβ brain homeostasis and clearance therapy.
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Abhay P
authors.initials: AP
authors.lastname: Sagare
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Halliday
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Pan
authors.initials: P
authors.lastname: Kong
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Kassandra
authors.initials: K
authors.lastname: Kisler
authors.affiliation: 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.
authors.forename: Ethan A
authors.initials: EA
authors.lastname: Winkler
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Ramanathan
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kanekiyo
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Nelly Chuqui
authors.initials: NC
authors.lastname: Owens
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Sanket V
authors.initials: SV
authors.lastname: Rege
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Si
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Ashim
authors.initials: A
authors.lastname: Ahuja
authors.affiliation: Department of Chemical, Biological and Bioengineering, North Carolina Agricultural and Technical State University, Greensboro, North Carolina, USA.
authors.forename: Donghui
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Miller
authors.affiliation: Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.affiliation: 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.
authors.forename: Manami
authors.initials: M
authors.lastname: Maeda
authors.affiliation: 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.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Maeda
authors.affiliation: 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.
authors.forename: Tohru
authors.initials: T
authors.lastname: Sugawara
authors.affiliation: 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.
authors.forename: Justin K
authors.initials: JK
authors.lastname: Ichida
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Berislav V
authors.initials: BV
authors.lastname: Zlokovic
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002196:Capillaries / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D034041:Monomeric Clathrin Assembly Proteins / Q000172:deficiency / Q000378:metabolism*; D039904:Pluripotent Stem Cells; D057900:Transcytosis
chemical_list: D016229:Amyloid beta-Peptides; D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human; C573094:PICALM protein, mouse