The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia

被引:0
作者
Mishra, Swati [1 ,2 ]
Morshed, Nader [3 ,4 ]
Sidhu, Sonia Beant [1 ,2 ]
Kinoshita, Chizuru [1 ,2 ]
Stevens, Beth [3 ,4 ,5 ]
Jayadev, Suman [2 ,6 ]
Young, Jessica E. [1 ,2 ]
机构
[1] Univ Washington, Dept Lab Med & Pathol, Seattle, WA 98195 USA
[2] Univ Washington, Inst Stem Cell & Regenerat Med, Seattle, WA 98195 USA
[3] Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA USA
[4] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA
[5] Howard Hughes Med Inst, Boston, MA USA
[6] Univ Washington, Dept Neurol, Seattle, WA USA
来源
关键词
Alzheimer's disease; hiPSC-derived microglia; lysosomes; phagocytosis; SORL1; SORTING RECEPTOR SORLA; MOUSE MODEL; CATHEPSIN-D; CYTOPLASMIC DOMAIN; EXOCYTOSIS; RETROMER; COMPLEX; ASSOCIATION; ASTROCYTES; SECRETION;
D O I
10.1002/glia.70009
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The SORL1 gene encodes the sortilin-related receptor protein SORLA, a sorting receptor that regulates endo-lysosomal trafficking of various substrates. Loss of function variants in SORL1 are causative for Alzheimer's disease (AD) and decreased expression of SORLA has been repeatedly observed in human AD brains. SORL1 is highly expressed in the central nervous system, including in microglia, the tissue-resident immune cells of the brain. Loss of SORLA leads to enlarged lysosomes in hiPSC-derived microglia-like cells (hMGLs). However, how SORLA deficiency contributes to lysosomal dysfunction in microglia and how this contributes to AD pathogenesis is not known. In this study, we show that loss of SORLA results in decreased lysosomal degradation and lysosomal enzyme activity due to altered trafficking of lysosomal enzymes in hMGLs. Phagocytic uptake of fibrillar amyloid beta 1-42 and synaptosomes is increased in SORLA-deficient hMGLs, but due to reduced lysosomal degradation, these substrates aberrantly accumulate in lysosomes. An alternative mechanism of lysosome clearance, lysosomal exocytosis, is also impaired in SORL1-deficient microglia, which may contribute to an altered immune response. Overall, these data suggest that SORLA has an important role in the proper trafficking of lysosomal hydrolases in hMGLs, which is critical for microglial function. This further substantiates the microglial endo-lysosomal network as a potential novel pathway through which SORL1 may increase AD risk and contribute to the development of AD. Additionally, our findings may inform the development of novel lysosome and microglia-associated drug targets for AD.
引用
收藏
页数:20
相关论文
共 114 条
[1]   An emerging interplay between extracellular vesicles and cytokines [J].
Aiello, Alessandra ;
Giannessi, Flavia ;
Percario, Zulema A. ;
Affabris, Eisabetta .
CYTOKINE & GROWTH FACTOR REVIEWS, 2020, 51 :49-60
[2]  
Akiyama H, 1999, GLIA, V25, P324, DOI 10.1002/(SICI)1098-1136(19990215)25:4<324::AID-GLIA2>3.0.CO
[3]  
2-5
[4]   2018 Alzheimer's disease facts and figures [J].
不详 .
ALZHEIMERS & DEMENTIA, 2018, 14 (03) :367-425
[5]   Modulation of Hematopoietic Lineage Specification Impacts TREM2 Expression in Microglia-Like Cells Derived From Human Stem Cells [J].
Amos, Peter J. ;
Fung, Susan ;
Case, Amanda ;
Kifelew, Jerusalem ;
Osnis, Leah ;
Smith, Carole L. ;
Green, Kevin ;
Naydenov, Alipi ;
Aloi, Macarena ;
Hubbard, Jesse J. ;
Ramakrishnan, Aravind ;
Garden, Gwenn A. ;
Jayadev, Suman .
ASN NEURO, 2017, 9 (04)
[6]   A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency [J].
Andersen, Olav M. ;
Bogh, Nikolaj ;
Landau, Anne M. ;
Ploen, Gro G. ;
Jensen, Anne Mette G. ;
Monti, Giulia ;
Ulhoi, Benedicte P. ;
Nyengaard, Jens R. ;
Jacobsen, Kirsten R. ;
Jorgensen, Margarita M. ;
Holm, Ida E. ;
Kristensen, Marianne L. ;
Alstrup, Aage Kristian O. ;
Hansen, Esben S. S. ;
Teunissen, Charlotte E. ;
Breidenbach, Laura ;
Droescher, Mathias ;
Liu, Ying ;
Pedersen, Hanne S. ;
Callesen, Henrik ;
Luo, Yonglun ;
Bolund, Lars ;
Brooks, David J. ;
Laustsen, Christoffer ;
Small, Scott A. ;
Mikkelsen, Lars F. ;
Sorensen, Charlotte B. .
CELL REPORTS MEDICINE, 2022, 3 (09)
[7]   Phospholipases C and A2 control lysosome-mediated IL-1β secretion:: Implications for inflammatory processes [J].
Andrei, C ;
Margiocco, P ;
Poggi, A ;
Lotti, LV ;
Torrisi, MR ;
Rubartelli, A .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (26) :9745-9750
[8]  
Andrews NW, 2017, METHODS MOL BIOL, V1594, P205, DOI 10.1007/978-1-4939-6934-0_13
[9]   Regulated secretion of conventional lysosomes [J].
Andrews, NW .
TRENDS IN CELL BIOLOGY, 2000, 10 (08) :316-321
[10]  
[Anonymous], 2012, Fiji: An Open-Source Platform for Biological-Image Analysis, DOI [10.1038/nmeth.2019, DOI 10.1038/NMETH.2019]