Microglial lipid droplet accumulation in tauopathy brain is regulated by neuronal AMPK

被引：42

作者：

Li, Yajuan ^{[1
]}

Munoz-Mayorga, Daniel ^{[2
]}

Nie, Yuhang ^{[2
]}

Kang, Ningxin ^{[2
]}

Tao, Yuren ^{[2
]}

Lagerwall, Jessica ^{[2
]}

Pernaci, Carla ^{[3
,4
]}

Curtin, Genevieve ^{[3
,4
]}

Coufal, Nicole G. ^{[3
,4
]}

Mertens, Jerome ^{[2
]}

Shi, Lingyan ^{[1
]}

Chen, Xu ^{[2
]}

机构：

[1] Univ Calif San Diego, Shu Chien Gene Lay Dept Bioengn, San Diego, CA 92093 USA

[2] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92093 USA

[3] Univ Calif San Diego, Dept Pediat, San Diego, CA USA

[4] Sanford Consortium Regenerat Med, San Diego, CA USA

来源：

CELL METABOLISM | 2024年 / 36卷 / 06期

基金：

美国国家卫生研究院;

关键词：

ACTIVATED PROTEIN-KINASE; TAU PHOSPHORYLATION; ALZHEIMERS-DISEASE; IN-VIVO; PATHWAY; DEGRADATION; AUTOPHAGY; TANGLES;

D O I：

10.1016/j.cmet.2024.03.014

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The accumulation of lipid droplets (LDs) in aging and Alzheimer's disease brains is considered a pathological phenomenon with unresolved cellular and molecular mechanisms. Utilizing stimulated Raman scattering (SRS) microscopy, we observed significant in situ LD accumulation in microglia of tauopathy mouse brains. SRS imaging, combined with deuterium oxide (D 2 O) labeling, revealed heightened lipogenesis and impaired lipid turnover within LDs in tauopathy fly brains and human neurons derived from induced pluripotent stem cells (iPSCs). Transfer of unsaturated lipids from tauopathy iPSC neurons to microglia induced LD accumulation, oxidative stress, inflammation, and impaired phagocytosis. Neuronal AMP -activated protein kinase (AMPK) inhibits lipogenesis and promotes lipophagy in neurons, thereby reducing lipid flux to microglia. AMPK depletion in prodromal tauopathy mice increased LD accumulation, exacerbated pro -inflammatory microgliosis, and promoted neuropathology. Our findings provide direct evidence of native, aberrant LD accumulation in tauopathy brains and underscore the critical role of AMPK in regulating brain lipid homeostasis.

引用

页码：1351 / 1370.e8

页数：29

共 100 条

[1] The Gene Ontology knowledgebase in 2023 [J].

Aleksander, Suzi A. ;

Balhoff, James ;

Carbon, Seth ;

Cherry, J. Michael ;

Drabkin, Harold J. ;

Ebert, Dustin ;

Feuermann, Marc ;

Gaudet, Pascale ;

Harris, Nomi L. ;

Hill, David P. ;

Lee, Raymond ;

Mi, Huaiyu ;

Moxon, Sierra ;

Mungall, Christopher J. ;

Muruganugan, Anushya ;

Mushayahama, Tremayne ;

Sternberg, Paul W. ;

Thomas, Paul D. ;

Van Auken, Kimberly ;

Ramsey, Jolene ;

Siegele, Deborah A. ;

Chisholm, Rex L. ;

Fey, Petra ;

Aspromonte, Maria Cristina ;

Nugnes, Maria Victoria ;

Quaglia, Federica ;

Tosatto, Silvio ;

Giglio, Michelle ;

Nadendla, Suvarna ;

Antonazzo, Giulia ;

Attrill, Helen ;

dos Santos, Gil ;

Marygold, Steven ;

Strelets, Victor ;

Tabone, Christopher J. ;

Thurmond, Jim ;

Zhou, Pinglei ;

Ahmed, Saadullah H. ;

Asanitthong, Praoparn ;

Luna Buitrago, Diana ;

Erdol, Meltem N. ;

Gage, Matthew C. ;

Ali Kadhum, Mohamed ;

Li, Kan Yan Chloe ;

Long, Miao ;

Michalak, Aleksandra ;

Pesala, Angeline ;

Pritazahra, Armalya ;

Saverimuttu, Shirin C. C. ;

Su, Renzhi .

GENETICS, 2023, 224 (01)

[2]

Alzheimer A, 1995, Clin Anat, V8, P429

[3] Aged lipid-laden microglia display impaired responses to stroke [J].

Arbaizar-Rovirosa, Maria ;

Pedragosa, Jordi ;

Lozano, Juan J. ;

Casal, Carme ;

Pol, Albert ;

Gallizioli, Mattia ;

Planas, Anna M. .

EMBO MOLECULAR MEDICINE, 2023, 15 (02)

[4] Gene Ontology: tool for the unification of biology [J].

Ashburner, M ;

Ball, CA ;

Blake, JA ;

Botstein, D ;

Butler, H ;

Cherry, JM ;

Davis, AP ;

Dolinski, K ;

Dwight, SS ;

Eppig, JT ;

Harris, MA ;

Hill, DP ;

Issel-Tarver, L ;

Kasarskis, A ;

Lewis, S ;

Matese, JC ;

Richardson, JE ;

Ringwald, M ;

Rubin, GM ;

Sherlock, G .

NATURE GENETICS, 2000, 25 (01) :25-29

[5] The Bewildering Effect of AMPK Activators in Alzheimer's Disease: Review of the Current Evidence [J].

Assefa, Brhane Teklebrhan ;

Tafere, Gebrehiwot Gebremedhin ;

Wondafrash, Dawit Zewdu ;

Gidey, Meles Tekie .

BIOMED RESEARCH INTERNATIONAL, 2020, 2020

[6] Antioxidant Role for Lipid Droplets in a Stem Cell Niche of Drosophila [J].

Bailey, Andrew P. ;

Koster, Grielof ;

Guillermier, Christelle ;

Hirst, Elizabeth M. A. ;

MacRae, James I. ;

Lechene, Claude P. ;

Postle, Anthony D. ;

Gould, Alex P. .

CELL, 2015, 163 (02) :340-353

[7] Laser tricks without labels [J].

Baker, Monya .

NATURE METHODS, 2010, 7 (04) :261-266

[8] Polyunsaturated fatty acids and their metabolites in brain function and disease [J].

Bazinet, Richard P. ;

Laye, Sophie .

NATURE REVIEWS NEUROSCIENCE, 2014, 15 (12) :771-785

[9] Opposite and redundant roles of the two Drosophila perilipins in lipid mobilization [J].

Bi, Junfeng ;

Xiang, Yanhui ;

Chen, Haiyang ;

Liu, Zhonghua ;

Groenke, Sebastian ;

Kuehnlein, Ronald P. ;

Huang, Xun .

JOURNAL OF CELL SCIENCE, 2012, 125 (15) :3568-3577

[10]

BLIGH EG, 1959, CAN J BIOCHEM PHYS, V37, P911

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