CoChat
Sign Up
PreprintCited by 38Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsLipid metabolism and biosynthesis

Amyloid β Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer’s Disease

Open access
Prakash, Priya, Manchanda, Palak, Paouri, Evi, Bisht, Kanchan, Sharma, Kaushik, Rajpoot, Jitika, Wendt, Victoria, Hossain, Ahad +22 more·2023·Alzheimer s & Dementia
DOI 10.1101/2023.06.04.543525PMC PMC10274698
Open this paper in CoChat — free accountOpen PDF

Abstract

Summary: Several microglia-expressed genes have emerged as top risk variants for Alzheimer’s disease (AD). Impaired microglial phagocytosis is one of the main proposed outcomes by which these AD-risk genes may contribute to neurodegeneration, but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here we show that microglia form lipid droplets (LDs) upon exposure to amyloid-beta (Aβ), and that their LD load increases with proximity to amyloid plaques in brains from human patients and the AD mouse model 5xFAD. LD formation is dependent on age and disease progression and is prominent in the hippocampus in mice and humans. Despite differences in microglial LD load between brain regions and sexes in mice, LD-laden microglia exhibited a deficit in Aβ phagocytosis. Unbiased lipidomic analysis identified a decrease in free fatty acids (FFAs) and a parallel increase in triacylglycerols (TGs) as the key metabolic transition underlying LD formation. DGAT2, a key enzyme for converting FFAs to TGs, promotes microglial LD formation and is increased in 5xFAD and human AD brains. Inhibition or degradation of DGAT2 improved microglial uptake of Aβ and drastically reduced plaque load in 5xFAD mice, respectively. These findings identify a new lipid-mediated mechanism underlying microglial dysfunction that could become a novel therapeutic target for AD.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1101/2023.06.04.543525

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 82

  1. [1]Serrano-Pozo A., Frosch M. P., Masliah E. & Hyman B. T. Neuropathological alterations in Alzheimer disease. Cold Spring Harb. Perspect. Med. 1, (2011). PMC3234452 22229116
  2. [2]Plascencia-Villa G. & Perry G. Status and future directions of clinical trials in Alzheimer’s disease. in International Review of Neurobiology vol. 154 3– 50 (2020). 32739008
  3. [3]Morris G. P., Clark I. A. & Vissel B. Inconsistencies and Controversies Surrounding the Amyloid Hypothesis of Alzheimer’s Disease. Acta Neuropathologica Communications vol. 2 1– 21 (2014). 25231068 PMC4207354
  4. [4]Bertram L. Genome-wide Association Analysis Reveals Putative Alzheimer’s Disease Susceptibility Loci in Addition to APOE. Am. J. Hum. Genet. 83, 623– 632 (2008). 18976728 PMC2668052
  5. [5]Hollingworth P. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat. Genet. 43, 429– 436 (2011). 21460840 PMC3084173
  6. [6]Naj A. C. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat. Genet. 43, 436– 443 (2011). 21460841 PMC3090745
  7. [7]Guerreiro R. TREM2 Variants in Alzheimer’s Disease. N. Engl. J. Med. 368, 117– 127 (2013). 23150934 PMC3631573
  8. [8]Jonsson T. Variant of TREM2 Associated with the Risk of Alzheimer’s Disease. N. Engl. J. Med. 368, 107– 116 (2013). 23150908 PMC3677583
  9. [9]Keren-Shaul H. A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell 169, 1276– 1290.e17 (2017). 28602351
  10. [10]Krasemann S. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity 47, 566– 581.e9 (2017). 28930663 PMC5719893
  11. [11]Nott A. Brain cell type–specific enhancer–promoter interactome maps and disease-risk association. Science (80-.). 366, 1134– 1139 (2019). PMC7028213 31727856
  12. [12]Wyss-Coray T. & Rogers J. Inflammation in Alzheimer disease-A brief review of the basic science and clinical literature. Cold Spring Harb. Perspect. Med. 2, a006346 (2012). 22315714 PMC3253025
  13. [13]Condello C., Yuan P., Schain A. & Grutzendler J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat. Commun. 6, 1– 14 (2015). PMC4311408 25630253
  14. [14]Yuan P. TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy. Neuron 90, 724– 739 (2016). 27196974 PMC4898967
  15. [15]Heneka M. T. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 14, 388– 405 (2015). 25792098 PMC5909703
  16. [16]Hickman S. E., Allison E. K. & El Khoury J. Microglial dysfunction and defective β-amyloid clearance pathways in aging alzheimer’s disease mice. J. Neurosci. 28, 8354– 8360 (2008). 18701698 PMC2597474
  17. [17]Krabbe G. Functional Impairment of Microglia Coincides with Beta-Amyloid Deposition in Mice with Alzheimer-Like Pathology. PLoS One 8, (2013). PMC3620049 23577177
  18. [18]Leyrolle Q., Layé S. & Nadjar A. Direct and indirect effects of lipids on microglia function. Neuroscience Letters vol. 708 134– 348 (2019). 31238131
  19. [19]Tremblay M. E. Remodeling of lipid bodies by docosahexaenoic acid in activated microglial cells. J. Neuroinflammation 13, 1– 18 (2016). 27220286 PMC4879742
  20. [20]Marschallinger J. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat. Neurosci. 23, 194– 208 (2020). 31959936 PMC7595134
  21. [21]Chausse B., Kakimoto P. A. & Kann O. Microglia and lipids: how metabolism controls brain innate immunity. Seminars in Cell and Developmental Biology vol. 112 137– 144 (2021). 32807643
  22. [22]Bourre J. M. Brain lipids and ageing. in Food for the Ageing Population: A volume in Woodhead Publishing Series in Food Science, Technology and Nutrition 219– 251 (2008). doi: 10.1533/9781845695484.2.219. · DOI · Paper page
  23. [23]Cantuti-Castelvetri L. Defective cholesterol clearance limits remyelination in the aged central nervous system. Science (80-.). 359, 684– 688 (2018). 29301957
  24. [24]Wong M. W. Dysregulation of lipids in Alzheimer’s disease and their role as potential biomarkers. Alzheimer’s and Dementia vol. 13 810– 827 (2017). 28242299
  25. [25]Tsai A. P. INPP5D expression is associated with risk for Alzheimer’s disease and induced by plaque-associated microglia. Neurobiol. Dis. 153, 105303 (2021). 33631273 PMC8082515
  26. [26]Wang Y. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061– 1071 (2015). 25728668 PMC4477963
  27. [27]Fitz N. F. Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer’s disease. Nat. Commun. 12, (2021). PMC8184801 34099706
  28. [28]Stelzmann R. A., Norman Schnitzlein H. & Reed Murtagh F. An english translation of alzheimer’s 1907 paper, “über eine eigenartige erkankung der hirnrinde”. Clin. Anat. 8, 429– 431 (1995). 8713166
  29. [29]Farese R. V. & Walther T. C. Lipid Droplets Finally Get a Little R-E-S-P-E-C-T. Cell vol. 139 855– 860 (2009). 19945371 PMC3097139
  30. [30]Fujimoto T. & Parton R. G. Not Just Fat: The Structure and Function of the Lipid Droplet. Cold Spring Harb. Perspect. Biol. 3, 1– 17 (2011). PMC3039932 21421923
  31. [31]Khatchadourian A., Bourque S. D., Richard V. R., Titorenko V. I. & Maysinger D. Dynamics and regulation of lipid droplet formation in lipopolysaccharide (LPS)-stimulated microglia. Biochim. Biophys. Acta 1821, 607– 17 (2012). 22289388
  32. [32]Urso C. J. & Zhou H. Palmitic acid lipotoxicity in microglia cells is ameliorated by unsaturated fatty acids. Int. J. Mol. Sci. 22, 90– 93 (2021). PMC8396597 34445796
  33. [33]Claes C. Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer’s disease. Mol. Neurodegener. 16, 50 (2021). 34301296 PMC8305935
  34. [35]Oblak A. L. Comprehensive Evaluation of the 5XFAD Mouse Model for Preclinical Testing Applications: A MODEL-AD Study. Front. Aging Neurosci. 13, (2021). PMC8346252 34366832
  35. [36]Merlini M. Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer’s Disease Model. Neuron 101, 1099– 1108.e6 (2019). 30737131 PMC6602536
  36. [37]Guttenplan K. A. Neurotoxic reactive astrocytes induce cell death via saturated lipids. Nature 599, 102– 107 (2021). 34616039 PMC12054010
  37. [38]Yu Y., Ramachandran P. V. & Wang M. C. Shedding new light on lipid functions with CARS and SRS microscopy. Biochim. Biophys. Acta - Mol. Cell Biol. Lipids 1841, 1120– 1129 (2014). PMC4285713 24576891
  38. [40]Itagaki S., McGeer P. L., Akiyama H., Zhu S. & Selkoe D. Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J. Neuroimmunol. 24, 173– 182 (1989). 2808689
  39. [41]Baron R., Babcock A. A., Nemirovsky A., Finsen B. & Monsonego A. Accelerated microglial pathology is associated with Aβ plaques in mouse models of Alzheimer’s disease. Aging Cell 13, 584– 595 (2014). 24641683 PMC4326940
  40. [42]Orre M. Isolation of glia from Alzheimer’s mice reveals inflammation anddysfunction. Neurobiol. Aging 35, 2746– 2760 (2014). 25002035
  41. [43]Prakash P. Monitoring phagocytic uptake of amyloid β into glial cell lysosomes in real time. Chem. Sci. 12, 10901– 10918 (2021). 34476070 PMC8372545
  42. [44]Yen C.-L. E., Stone S. J., Koliwad S., Harris C. & Farese R. V. Thematic review series: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. J. Lipid Res. 49, 2283– 301 (2008). 18757836 PMC3837458
  43. [45]Chitraju C., Walther T. C. & Farese R. V. The triglyceride synthesis enzymes DGAT1 and DGAT2 have distinct and overlapping functions in adipocytes. J. Lipid Res. 60, 1112– 1120 (2019). 30936184 PMC6547635
  44. [46]Wilfling F. Triacylglycerol synthesis enzymes mediate lipid droplet growth by relocalizing from the ER to lipid droplets. Dev. Cell 24, 384– 399 (2013). 23415954 PMC3727400
  45. [47]Kuerschner L., Moessinger C. & Thiele C. Imaging of lipid biosynthesis: How a neutral lipid enters lipid droplets. Traffic 9, 338– 352 (2008). 18088320
  46. [48]Stone S. J. The endoplasmic reticulum enzyme DGAT2 is found in mitochondria-associated membranes and has a mitochondrial targeting signal that promotes its association with mitochondria. J. Biol. Chem. 284, 5352– 5361 (2009). 19049983 PMC2643492
  47. [50]Uriarte Huarte O., Richart L., Mittelbronn M. & Michelucci A. Microglia in Health and Disease: The Strength to Be Diverse and Reactive. Frontiers in Cellular Neuroscience vol. 15 (2021). PMC8044310 33867943
  48. [51]Gordon G. B. Saturated free fatty acid toxicity. II. Lipid accumulation, ultrastructural alterations, and toxicity in mammalian cells in culture. Exp. Mol. Pathol. 27, 262– 276 (1977). 561704
  49. [52]Listenberger L. L. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc. Natl. Acad. Sci. 100, 3077– 3082 (2003). 12629214 PMC152249
  50. [53]Schönfeld P. & Reiser G. Why does brain metabolism not favor burning of fatty acids to provide energy-Reflections on disadvantages of the use of free fatty acids as fuel for brain. Journal of Cerebral Blood Flow and Metabolism vol. 33 1493– 1499 (2013). 23921897 PMC3790936
  51. [54]Sultana R., Perluigi M. & Butterfield D. A. Lipid peroxidation triggers neurodegeneration: A redox proteomics view into the Alzheimer disease brain. Free Radical Biology and Medicine vol. 62 157– 169 (2013). 23044265 PMC3573239
  52. [55]Reynolds I. J. & Hastings T. G. Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. J. Neurosci. 15, 3318– 3327 (1995). 7751912 PMC6578215
  53. [56]Carlesimo G. A. Atrophy of presubiculum and subiculum is the earliest hippocampal anatomical marker of Alzheimer’s disease. Alzheimer’s Dement. (Amsterdam, Netherlands) 1, 24– 32 (2015). PMC4876901 27239489
  54. [57]Li N., Lizardo D. Y. & Atilla-Gokcumen G. E. Specific Triacylglycerols Accumulate via Increased Lipogenesis during 5-FU-Induced Apoptosis. ACS Chem. Biol. 11, 2583– 2587 (2016). 27428610
  55. [58]Lizardo D. Y., Lin Y. L., Gokcumen O. & Atilla-Gokcumen G. E. Regulation of lipids is central to replicative senescence. Mol. Biosyst. 13, 498– 509 (2017). 28128379
  56. [59]Ogrodnik M. Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis. Cell Metab. 29, 1061– 1077.e8 (2019). 30612898 PMC6509403
  57. [60]Mawuenyega K. G. Decreased clearance of CNS β-amyloid in Alzheimer’s disease. Science (80-.). 330, 1774 (2010). PMC3073454 21148344
  58. [61]Liu Z., Condello C., Schain A., Harb R. & Grutzendler J. CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-β phagocytosis. J. Neurosci. 30, 17091– 17101 (2010). 21159979 PMC3077120
  59. [62]Mandrekar S. Microglia mediate the clearance of soluble aβ through fluid phase macropinocytosis. J. Neurosci. 29, 4252– 4262 (2009). 19339619 PMC3034143
  60. [63]Njie, e. M. G. Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol. Aging 33, 195.e1– 195.e12 (2012). PMC4162517 20580465
  61. [64]Baik S. H. A Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer’s Disease. Cell Metab. 30, 493– 507.e6 (2019). 31257151
  62. [65]Pluvinage J. V. CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature 568, 187– 192 (2019). 30944478 PMC6574119
  63. [66]Huang Y. Microglia use TAM receptors to detect and engulf amyloid β plaques. Nat. Immunol. 22, 586– 594 (2021). 33859405 PMC8102389
  64. [67]Castoldi A. Triacylglycerol synthesis enhances macrophage inflammatory function. Nat. Commun. 11, (2020). PMC7427976 32796836
  65. [68]Chandak P. G. Efficient phagocytosis requires triacylglycerol hydrolysis by adipose triglyceride lipase. J. Biol. Chem. 285, 20192– 20201 (2010). 20424161 PMC2888432
  66. [69]Bohlen C. J., Bennett F. C. & Bennett M. L. Isolation and Culture of Microglia. Curr. Protoc. Immunol. 125, e70 (2019). 30414379 PMC6510657
  67. [70]Prakash P., Lantz T. C., Jethava K. P. & Chopra G. Rapid, Refined, and Robust Method for Expression, Purification, and Characterization of Recombinant Human Amyloid beta 1–42. Methods Protoc. 2, 48 (2019). 31181684 PMC6632169
  68. [72]Xie Z., Ferreira C. R., Virequ A. A. & Cooks R. G. Multiple reaction monitoring profiling (MRM profiling): Small molecule exploratory analysis guided by chemical functionality. Chem. Phys. Lipids 235, 105048 (2021). 33561466
  69. [73]Cordeiro F. B. Multiple reaction monitoring (MRM)-profiling for biomarker discovery applied to human polycystic ovarian syndrome. Rapid Commun. Mass Spectrom. 31, 1462– 1470 (2017). 28656689
  70. [74]de Lima C. B. Comprehensive lipid profiling of early stage oocytes and embryos by MRM profiling. J. Mass Spectrom. 53, 1247– 1252 (2018). 30325087
  71. [75]Fahy E. Update of the LIPID MAPS comprehensive classification system for lipids. J. Lipid Res. 50, S9– S14 (2009). 19098281 PMC2674711
  72. [76]Guttenplan K. A. Neurotoxic reactive astrocytes induce cell death via saturated lipids. Nature 1– 6 (2021). PMC12054010 34616039
  73. [77]Robinson M. D., McCarthy D. J. & Smyth G. K. edgeR: A Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139– 140 (2009). 19910308 PMC2796818
  74. [78]McCarthy D. J., Chen Y. & Smyth G. K. Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res. 40, 4288– 4297 (2012). 22287627 PMC3378882
  75. [80]Randolph C. E., Foreman D. J., Blanksby S. J. & McLuckey S. A. Generating Fatty Acid Profiles in the Gas Phase: Fatty Acid Identification and Relative Quantitation Using Ion/Ion Charge Inversion Chemistry. Anal. Chem. 91, 9032– 9040 (2019). 31199126 PMC6882335
  76. [81]Randolph C. E., Marshall D. L., Blanksby S. J. & McLuckey S. A. Charge-switch derivatization of fatty acid esters of hydroxy fatty acids via gas-phase ion/ion reactions. Anal. Chim. Acta 1129, 31– 39 (2020). 32891388 PMC7477303
  77. [82]Xia Y., Wu J., McLuckey S. A., Londry F. A. & Hager J. W. Mutual storage mode ion/ion reactions in a hybrid linear ion trap. J. Am. Soc. Mass Spectrom. 16, 71– 81 (2005). 15653365
  78. [83]Xia Y., Liang X. & McLuckey S. A. Pulsed dual electrospray ionization for ion/ion reactions. J. Am. Soc. Mass Spectrom. 16, 1750– 1756 (2005). 16182558
  79. [84]Londry F. A. & Hager J. W. Mass selective axial ion ejection from a linear quadrupole ion trap. J. Am. Soc. Mass Spectrom. 2003 1410 14, 1130– 1147 (2003). 14530094
  80. [85]Xia J., Wishart D. S. & Valencia A. MetPA: a web-based metabolomics tool for pathway analysis and visualization. Bioinformatics 26, 2342– 2344 (2010). 20628077
  81. [86]DeVos S. L. & Miller T. M. Direct Intraventricular Delivery of Drugs to the Rodent Central Nervous System. J. Vis. Exp. (2013) doi: 10.3791/50326-v. PMC3679837 23712122 · DOI
  82. [87]Spandl J., White D. J., Peychl J. & Thiele C. Live cell multicolor imaging of lipid droplets with a new dye, LD540. Traffic (2009) doi: 10.1111/j.1600-0854.2009.00980.x. 19765264 · DOI

Cited by

Sorted by citations

Authors
Prakash, P., Manchanda, P., Paouri, E., Bisht, K., Sharma, K., Rajpoot, J., Wendt, V., Hossain, A., Wijewardhane, P. R., Randolph, C. E., Chen, Y., Stanko, S., Gasmi, N., Gjojdeshi, A., Card, S., Fine, J., Jethava, K. P., Clark, M. G., Dong, B., Ma, S., Crockett, A., Thayer, E. A., Nicolas, M., Davis, R., Hardikar, D., Allende, D., Prayson, R. A., Zhang, C., Davalos, D., & Chopra, G.
Affiliations
  • Purdue University West Lafayette (US)
  • Cleveland Clinic (US)
Corresponding author
  • Davalos, Dimitrios
  • Chopra, Gaurav
ORCID
Venue
Alzheimer s & Dementia
Publisher
openRxiv
Published
2023-06-06
Volume
19
Issue
S13
ISSN
1552-5260 (ISSN-L)
DOI
10.1101/2023.06.04.543525
PMC
PMC10274698
OpenAlex
W4390199705
Cited by
38
References
3
Citations by year
2026: 8 · 2025: 18 · 2024: 11 · 2023: 1
FWCI
3.89
Type
journal article
Language
en
Open access
Licence
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations
  • Alzheimer s & Dementia (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • U.S. Department of Defense (W81XWH2010665, UL1TR002529)
  • Eli Lilly and Company
  • Purdue University (P30 CA023168)
  • Cleveland Clinic
  • Purdue University Center for Cancer Research (P30 CA 023168)
  • National Institutes of Health (1rf1mh128866-01, UL1TR002529, CA023168)
  • National Institute on Alcohol Abuse and Alcoholism (P50AA024333)
  • National Institute of Mental Health (R01MH128866)
  • National Cancer Institute (P30CA023168)
  • National Institute of Neurological Disorders and Stroke (R01NS112526)
  • National Center for Advancing Translational Sciences
  • U.S. Army Medical Research Acquisition Activity (W81XWH2010665)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
amyloid-beta, lipid droplets

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review