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

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