CoChat
Sign Up
Cited by 94Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsPhagocytosis and Immune Regulation

Naturally-aged microglia exhibit phagocytic dysfunction accompanied by gene expression changes reflective of underlying neurologic disease

Open access
Thomas, Alyssa L., Lehn, Maria A., Janssen, Edith M., Hildeman, David A., Chougnet, Claire A.·2022·Scientific Reports
DOI 10.1038/s41598-022-21920-yPMC PMC9663419
Open this paper in CoChat — free accountOpen PDF

Abstract

Age-associated microglial dysfunction contributes to the accumulation of amyloid-β (Aβ) plaques in Alzheimer’s disease. Although several studies have shown age-related declines in the phagocytic capacity of myeloid cells, relatively few have examined phagocytosis of normally aged microglia. Furthermore, much of the existing data on aging microglial function have been generated in accelerated genetic models of Alzheimer’s disease. Here we found that naturally aged microglia phagocytosed less Aβ over time. To gain a better understanding of such dysfunction, we assessed differences in gene expression between young and old microglia that either did or did not phagocytose Aβ. Young microglia had both phagocytic and neuronal maintenance signatures indicative of normal microglial responses, whereas, old microglia, regardless of phagocytic status, exhibit signs of broad dysfunction reflective of underlying neurologic disease states. We also found downregulation of many phagocytic receptors on old microglia, including TREM2, an Aβ phagocytic receptor. TREM2 protein expression was diminished in old microglia and loss of TREM2 + microglia was correlated with impaired Aβ uptake, suggesting a mechanism for phagocytic dysfunction in old microglia. Combined, our work reveals that normally aged microglia have broad changes in gene expression, including defects in Aβ phagocytosis that likely underlies the progression to neurologic disease.

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 · 10.1038/s41598-022-21920-y

Cites

16 of 16 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?

  • Autophagy and microglial phagocytosis are impaired in AD and aged brains.

    “Extensive evidence shows that autophagy and microglial phagocytosis are impaired in AD and aged brains [24, 30, 94, 103].”

    From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [94]

    The Introduction links microglial phagocytic deficiencies to Alzheimer’s disease progression, and the Results and discussion (‘Loss of phagocytic capacity in microglia from aged mice’; page unavailable) report reduced Aβ uptake by microglia from aged mice. The paper does not report impaired autophagy in AD or aged brains; a search for ‘autophagy’ found the term only in a reference title. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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: 44

  1. [1]Walsh DM Selkoe DJ Deciphering the molecular basis of memory failure in Alzheimer’s disease Neuron 2004 44 181 193 15450169
  2. [2]Selkoe DJ The genetics and molecular pathology of Alzheimer’s disease: Roles of amyloid and the presenilins Neurol. Clin. 2000 18 903 921 11072267
  3. [3]Mawuenyega KG Decreased clearance of CNS β-amyloid in Alzheimer’s disease Science 2010 330 1774 1774 21148344 PMC3073454
  4. [4]Tajbakhsh A Apoptotic neurons and amyloid-beta clearance by phagocytosis in Alzheimer’s disease: Pathological mechanisms and therapeutic outlooks Eur. J. Pharmacol. 2021 895 173873 33460611
  5. [5]Fiala M Ineffective phagocytosis of amyloid-β by macrophages of Alzheimer’s disease patients J. Alzheimers Dis. 2005 7 221 232 16006665
  6. [7]Scheltens P Alzheimer’s disease Lancet 2016 388 505 517 26921134
  7. [10]Ritzel RM Age-and location-related changes in microglial function Neurobiol. Aging. 2015 36 2153 2163 25816747
  8. [12]Linehan E Aging impairs peritoneal but not bone marrow-derived macrophage phagocytosis Aging Cell 2014 13 699 708 24813244 PMC4326936
  9. [13]De La Fuente M Changes in the macrophage function with aging Comp. Biochem. Physiol. A Comp. Physiol. 1985 81 935 938 2863082
  10. [14]Grolleau-Julius A Garg MR Mo R Stoolman LL Yung RL Effect of aging on bone marrow-derived murine CD11c+ CD4− CD8α− dendritic cell function J. Gerontol. A Biol. Sci. Med. Sci. 2006 61 1039 1047 17077196
  11. [15]Pösel C Möller K Boltze J Wagner D-C Weise G Isolation and flow cytometric analysis of immune cells from the ischemic mouse brain JoVE. 2016 108 e53658 PMC4828148 26967380
  12. [16]Chakrabarty P IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior Neuron 2015 85 519 533 25619653 PMC4320003
  13. [18]Rapp SJ Dershem V Zhang X Schutte SC Chariker ME Varying negative pressure wound therapy acute effects on human split-thickness autografts J. Burn Care Res. 2020 41 104 112 31420676
  14. [19]Walsh KB Intracerebral hemorrhage induces inflammatory gene expression in peripheral blood: Global transcriptional profiling in intracerebral hemorrhage patients DNA Cell Biol. 2019 38 660 669 31120332 PMC6909779
  15. [23]Dobin A STAR: Ultrafast universal RNA-seq aligner Bioinformatics 2012 29 15 21 23104886 PMC3530905
  16. [26]Liao Y Smyth GK Shi W The R package Rsubread is easier, faster, cheaper and better for alignment and quantification of RNA sequencing reads Nucleic Acids Res. 2019 47 e47 e47 30783653 PMC6486549
  17. [27]Love MI Huber W Anders S Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Genome Biol. 2014 15 550 25516281 PMC4302049
  18. [29]Chen J Bardes EE Aronow BJ Jegga AG ToppGene suite for gene list enrichment analysis and candidate gene prioritization Nucleic Acids Res. 2009 37 W305 W311 19465376 PMC2703978
  19. [30]Selkoe DJ Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer’s disease Annu. Rev. Cell Biol. 1994 10 373 403 7888181
  20. [31]Majumdar A Degradation of fibrillar forms of Alzheimer’s amyloid β-peptide by macrophages Neurobiol. Aging 2008 29 707 715 17222479 PMC2424018
  21. [32]Chung H Brazil MI Soe TT Maxfield FR Uptake, degradation, and release of fibrillar and soluble forms of Alzheimer’s amyloid β-peptide by microglial cells J. Biol. Chem. 1999 274 32301 32308 10542270
  22. [35]Hickman SE The microglial sensome revealed by direct RNA sequencing Nat. Neurosci. 2013 16 1896 1905 24162652 PMC3840123
  23. [36]Goitre, L., Trapani, E., Trabalzini, L. & Retta, S.F. The Ras superfamily of small GTPases: The unlocked secrets. In: Ras signaling, 1–18 (2014). 24470015
  24. [37]Arrazola Sastre A Luque Montoro M Lacerda HM Llavero F Zugaza JL Small GTPases of the Rab and Arf families: Key regulators of intracellular trafficking in neurodegeneration Int. J. Mol. Sci. 2021 22 4425 33922618 PMC8122874
  25. [38]Marques L Johnson AA Stolzing A Doxorubicin generates senescent microglia that exhibit altered proteomes, higher levels of cytokine secretion, and a decreased ability to internalize amyloid β Exp. Cell Res. 2020 395 112203 32738344
  26. [39]Lumeng CN Aging is associated with an increase in T cells and inflammatory macrophages in visceral adipose tissue J. Immunol. 2011 187 6208 6216 22075699 PMC3237772
  27. [41]Nguyen PT Microglial remodeling of the extracellular matrix promotes synapse plasticity Cell 2020 182 388 403.e315 32615087 PMC7497728
  28. [42]Crapser JD Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington’s disease Brain 2020 143 266 288 31848580 PMC6935750
  29. [43]Wake H Moorhouse AJ Jinno S Kohsaka S Nabekura J Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals J. Neurosci. 2009 29 3974 3980 19339593 PMC6665392
  30. [46]Silvin A Ginhoux F Microglia heterogeneity along a spatio–temporal axis: More questions than answers Glia 2018 66 2045 2057 30144321
  31. [47]Mathys H Temporal tracking of microglia activation in neurodegeneration at single-cell resolution Cell Rep. 2017 21 366 380 29020624 PMC5642107
  32. [49]Gómez-Nicola D Fransen NL Suzzi S Perry VH Regulation of microglial proliferation during chronic neurodegeneration J. Neurosci. 2013 33 2481 2493 23392676 PMC6619184
  33. [50]Li T Proliferation of parenchymal microglia is the main source of microgliosis after ischaemic stroke Brain 2013 136 3578 3588 24154617
  34. [51]Hu Y Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology Cell Rep. 2021 35 109228 34107254 PMC8206957
  35. [53]Qian M Shen X Wang H The distinct role of ADAM17 in APP proteolysis and microglial activation related to Alzheimer’s disease Cell. Mol. Neurobiol. 2016 36 471 482 26119306 PMC11482503
  36. [54]Zhao Y TREM2 is a receptor for β-amyloid that mediates microglial function Neuron 2018 97 1023 1031.e1027 29518356 PMC5889092
  37. [55]Bhattacharjee S Zhao Y Dua P Rogaev EI Lukiw WJ microRNA-34a-mediated down-regulation of the microglial-enriched triggering receptor and phagocytosis-sensor TREM2 in age-related macular degeneration PLoS ONE 2016 11 e0150211 26949937 PMC4780721
  38. [57]Perez SE Neocortical and hippocampal TREM2 protein levels during the progression of Alzheimer’s disease Neurobiol. Aging 2017 54 133 143 28365005 PMC6344038
  39. [58]Jiang T Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mouse model of Alzheimer’s disease Neuropsychopharmacology 2014 39 2949 2962 25047746 PMC4229581
  40. [59]Matarin M A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology Cell Rep. 2015 10 633 644 25620700
  41. [62]Schoch KM Acute Trem2 reduction triggers increased microglial phagocytosis, slowing amyloid deposition in mice Proc. Natl. Acad. Sci. 2021 118 e2100356118 34187891 PMC8271763
  42. [63]Huh S The reemergence of long-term potentiation in aged Alzheimer’s disease mouse model Sci. Rep. 2016 6 1 10 27377368 PMC4932605
  43. [64]Bennett RE Partial reduction of microglia does not affect tau pathology in aged mice J. Neuroinflammation 2018 15 1 11 30413160 PMC6230271
  44. [65]Zallo F Gardenal E Verkhratsky A Rodríguez JJ Loss of calretinin and parvalbumin positive interneurones in the hippocampal CA1 of aged Alzheimer’s disease mice Neurosci. Lett. 2018 681 19 25 29782955

Cited by

Sorted by citations

Authors
Thomas, A. L., Lehn, M. A., Janssen, E. M., Hildeman, D. A., & Chougnet, C. A.
Affiliations
Cincinnati Children's Hospital Medical Center (US)
Corresponding author
  • Hildeman, David A.
  • Chougnet, Claire A.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2022-11-14
Volume
12
Issue
1
Pages
19471-19471
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-022-21920-y
PMC
PMC9663419
OpenAlex
W4308968236
Cited by
94
References
16
Citations by year
2026: 24 · 2025: 34 · 2024: 28 · 2023: 6 · 2022: 2
FWCI
6.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute of Aging (R01AG053498)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
microglial aging, phagocytosis, amyloid-beta, Alzheimer's disease, TREM2, phagocytic receptors, microglial gene expression, microglial dysfunction, neurodegeneration
MeSH terms
Alzheimer Disease, Animals, Disease Models, Animal, Phagocytosis, Gene Expression, Amyloid beta-Peptides, Microglia, Plaque, Amyloid

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