Microglial lipid droplet accumulation in tauopathy brain is regulated by neuronal AMPK
Open accessAbstract
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.
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Lipid droplet accumulation is considered a marker of inflammation in microglia during aging and Alzheimer's disease.
“the accumulation of which is considered a marker of inflammation in microglia during aging and Alzheimer’s disease32–35”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [33]
Cites
A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
Bligh, E. G., & Dyer, W. J. (1959) · Canadian Journal of Biochemistry and Physiology · doi:10.1139/o59-099 · Cited by 54,751 · see citing works
Pankiv, S., Clausen, T. H., Lamark, T., Brech, A., Bruun, J.-A., Outzen, H., Øvervatn, A., Bjørkøy, G., & Johansen, T. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702824200 · Cited by 4,578 · see citing works
The AMPK signalling pathway coordinates cell growth, autophagy and metabolism
Mihaylova, M. M., & Shaw, R. J. (2011) · Nature Cell Biology · doi:10.1038/ncb2329 · Cited by 2,923 · see citing works
Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model
Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S.-M., Iwata, N., Saido, T. C., Maeda, J., Suhara, T., Trojanowski, J. Q., & Lee, V. M.-Y. (2007) · Neuron · doi:10.1016/j.neuron.2007.01.010 · Cited by 2,208 · see citing works
Marschallinger, J., Iram, T., Zardeneta, M., Lee, S. E., Lehallier, B., Haney, M. S., Pluvinage, J. V., Mathur, V., Hahn, O., Morgens, D. W., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-019-0566-1 · Cited by 1,384 · see citing works
Simpson, D. S. A., & Oliver, P. L. (2020) · Antioxidants · doi:10.3390/antiox9080743 · Cited by 1,044 · see citing works
Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity
Ioannou, M. S., Jackson, J., Sheu, S.-H., Chang, C.-L., Weigel, A. V., Liu, H., Pasolli, H. A., Xu, C. S., Pang, S., Matthies, D., et al. (2019) · Cell · doi:10.1016/j.cell.2019.04.001 · Cited by 760 · see citing works
APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia
Haney, M. S., Pálovics, R., Munson, C. N., Long, C., Johansson, P. K., Yip, O., Dong, W., Rawat, E., West, E., Schlachetzki, J. C. M., et al. (2024) · Nature · doi:10.1038/s41586-024-07185-7 · Cited by 536 · see citing works
ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism
Qi, G., Mi, Y., Shi, X., Gu, H., Brinton, R. D., & Yin, F. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108572 · Cited by 379 · see citing works
Culmsee, C., monnig, J., Kemp, B. E., & Mattson, M. P. (2001) · Journal of Molecular Neuroscience · doi:10.1385/jmn:17:1:45 · Cited by 340 · see citing works
<i>APOE4</i> disrupts intracellular lipid homeostasis in human iPSC-derived glia
Sienski, G., Narayan, P., Bonner, J. M., Kory, N., Boland, S., Arczewska, A. A., Ralvenius, W. T., Akay, L., Lockshin, E., He, L., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.aaz4564 · Cited by 336 · see citing works
Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity
Victor, M. B., Leary, N., Luna, X., Meharena, H. S., Scannail, A. N., Bozzelli, P. L., Samaan, G., Murdock, M. H., von Maydell, D., Effenberger, A. H., et al. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.07.005 · Cited by 316 · see citing works
Lipid and Lipoprotein Metabolism in Microglia
Loving, B. A., & Bruce, K. D. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00393 · Cited by 255 · see citing works
Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients
Mertens, J., Herdy, J. R., Traxler, L., Schafer, S. T., Schlachetzki, J. C. M., Böhnke, L., Reid, D. A., Lee, H., Zangwill, D., Fernandes, D. P., et al. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.04.004 · Cited by 240 · see citing works
Self-citationClaes, C., Danhash, E. P., Hasselmann, J., Chadarevian, J. P., Shabestari, S. K., England, W. E., Lim, T. E., Hidalgo, J. L. S., Spitale, R. C., Davtyan, H., et al. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00473-0 · Cited by 197 · see citing works
Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation
Farmer, B., Kluemper, J., & Johnson, L. (2019) · Cells · doi:10.3390/cells8020182 · Cited by 164 · see citing works
AMPK activation regulates neuronal structure in developing hippocampal neurons
Ramamurthy, S., Chang, E., Cao, Y., Zhu, J., & Ronnett, G. V. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2013.11.048 · Cited by 65 · see citing works
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INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia
Terzioglu, G., Karp, E. S., Heuer, S. E., Chadarevian, J. P., Ahsan, F. M., Haage, V. C., Davtyan, H., Fogo, G. M., Curle, A. J., Ashour, N., et al. (2025) · doi:10.1101/2025.10.27.684632 · Cited by 3 · see citing works
- Authors
- Li, Y., Munoz-Mayorga, D., Nie, Y., Kang, N., Tao, Y., Lagerwall, J., Pernaci, C., Curtin, G., Coufal, N. G., Mertens, J., Shi, L., & Chen, X.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Shi, Lingyan
- Chen, Xu
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2024-06
- Volume
- 36
- Issue
- 6
- Pages
- 1351-1370.e8
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC11153007
- OpenAlex
- W4395052805
- Cited by
- 160
- References
- 17
- Citations by year
- 2026: 67 · 2025: 78 · 2024: 15
- FWCI
- 45.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 368 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIA (R01AG074273, R21NS125395, R01NS111039, R01AG078185, R01 GM149976)
- National Institutes of Health
- University of California, San Diego
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- tauopathy, lipogenesis, lipophagy, lipid turnover, unsaturated lipids, microglial activation, oxidative stress, neuroinflammation, phagocytosis
- MeSH terms
- Animals, Brain, Drosophila, Humans, Male, Mice, Inbred C57BL, Neurons, Microglia, Tauopathies, Mice, AMP-Activated Protein Kinases, Induced Pluripotent Stem Cells, Lipid Droplets
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