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

被引：319

作者：

Zhao, Zhen ^{[1
,2
]}

Sagare, Abhay P. ^{[1
,2
]}

Ma, Qingyi ^{[1
,2
]}

Halliday, Matthew R. ^{[1
,2
]}

Kong, Pan ^{[1
,2
]}

Kisler, Kassandra ^{[1
,2
]}

Winkler, Ethan A. ^{[1
,2
,3
]}

Ramanathan, Anita ^{[1
,2
]}

Kanekiyo, Takahisa ^{[4
]}

Bu, Guojun ^{[4
]}

Owens, Nelly Chuqui ^{[1
,2
]}

Rege, Sanket V. ^{[1
,2
]}

Si, Gabriel ^{[1
,2
]}

Ahuja, Ashim ^{[1
,2
]}

Zhu, Donghui ^{[5
]}

Miller, Carol A. ^{[6
]}

Schneider, Julie A. ^{[7
]}

Maeda, Manami ^{[8
,9
]}

Maeda, Takahiro ^{[8
,9
]}

Sugawara, Tohru ^{[10
,11
]}

Ichida, Justin K. ^{[10
,11
]}

Zlokovic, Berislav V. ^{[1
,2
]}

机构：

[1] Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Los Angeles, CA 90033 USA

[2] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA

[3] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA

[4] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[5] N Carolina Agr & Tech State Univ, Dept Chem Biol & Bioengn, Greensboro, NC 27411 USA

[6] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA

[7] Rush Univ, Med Ctr, Alzheimers Dis Ctr, Chicago, IL 60612 USA

[8] City Hope Natl Med Ctr, Div Hematopoiet Stem Cell & Leukemia Res, Beckman Res Inst, Duarte, CA USA

[9] Harvard Univ, Sch Med, Div Hematol, Dept Med,Brigham & Womens Hospital, Boston, MA USA

[10] Univ So Calif, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA USA

[11] Univ So Calif, Dept Stem Cell Biol & Regenerat Med, Los Angeles, CA USA

来源：

NATURE NEUROSCIENCE | 2015年 / 18卷 / 07期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; ALZHEIMERS-DISEASE; ENDOCYTIC TRAFFICKING; SUSCEPTIBILITY LOCI; IDENTIFIES VARIANTS; IN-VIVO; CLATHRIN; CELLS; PROTEIN; RECEPTOR;

D O I：

10.1038/nn.4025

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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-beta (A beta) pathology and cognitive impairment. Moreover, Picalm deficiency diminished A beta clearance across the murine blood-brain barrier (BBB) and accelerated A beta 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 A beta bound to the low density lipoprotein receptor related protein-1, a key A beta clearance receptor, and guided A beta trafficking to Rab5 and Rab11, leading to A beta endothelial transcytosis and clearance. PICALM levels and A beta 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 A beta clearance. Thus, PICALM regulates A beta BBB transcytosis and clearance, which has implications for A beta brain homeostasis and clearance therapy.

引用

页码：978 / +

页数：13

共 50 条

[41] Intracellular transport and regulation of transcytosis across the blood-brain barrier
Villasenor, Roberto
Lampe, Josephine
Schwaninger, Markus
Collin, Ludovic
CELLULAR AND MOLECULAR LIFE SCIENCES, 2019, 76 (06) : 1081 - 1092
[42] Protein engineering approaches for regulating blood-brain barrier transcytosis
Goulatis, Loukas I.
Shusta, Eric V.
CURRENT OPINION IN STRUCTURAL BIOLOGY, 2017, 45 : 109 - 115
[43] Mechanisms of receptor-mediated transcytosis at the blood-brain barrier
Baghirov, Habib
JOURNAL OF CONTROLLED RELEASE, 2025, 381
[44] Chemical biology tools for probing transcytosis at the blood-brain barrier
Beard, Rhiannon
Gaboriau, David C. A.
Gee, Antony D.
Tate, Edward W.
CHEMICAL SCIENCE, 2019, 10 (46) : 10772 - 10778
[45] The Physiological Characteristics and Transcytosis Mechanisms of the Blood-Brain Barrier (BBB)
de Lange, Elizabeth C. M.
CURRENT PHARMACEUTICAL BIOTECHNOLOGY, 2012, 13 (12) : 2319 - 2327
[46] Suppression of transcytosis regulates zebrafish blood-brain barrier function
O'Brown, Natasha M.
Megason, Sean G.
Gu, Chenghua
ELIFE, 2019, 8
[47] TNF-α and IL-1β Modulate Blood-Brain Barrier Permeability and Decrease Amyloid-β Peptide Efflux in a Human Blood-Brain Barrier Model
Versele, Romain
Sevin, Emmanuel
Gosselet, Fabien
Fenart, Laurence
Candela, Pietra
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2022, 23 (18)
[48] Relationship Between Amyloid-β Deposition and Blood-Brain Barrier Dysfunction in Alzheimer's Disease
Wang, Dong
Chen, Fanglian
Han, Zhaoli
Yin, Zhenyu
Ge, Xintong
Lei, Ping
FRONTIERS IN CELLULAR NEUROSCIENCE, 2021, 15
[49] Nanoparticulate flurbiprofen reduces amyloid-β42 generation in an in vitro blood-brain barrier model
Meister, Sabrina
Zlatev, Iavor
Stab, Julia
Docter, Dominic
Baches, Sandra
Stauber, Roland H.
Deutsch, Mordechai
Schmidt, Reinhold
Ropele, Stefan
Windisch, Manfred
Langer, Klaus
Wagner, Sylvia
von Briesen, Hagen
Weggen, Sascha
Pietrzik, Claus U.
ALZHEIMERS RESEARCH & THERAPY, 2013, 5 (06)
[50] Blood-brain barrier permeability correlates with medial temporal lobe atrophy but not with amyloid-β protein transport across the blood-brain barrier in Alzheimer's disease
Matsumoto, Yasuko
Yanase, Daisuke
Noguchi-Shinohara, Moeko
Ono, Kenjiro
Yoshita, Mitsuhiro
Yamada, Masahito
DEMENTIA AND GERIATRIC COGNITIVE DISORDERS, 2007, 23 (04) : 241 - 245

← 1 2 3 4 5 →