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Cited by 95Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurogenesis and neuroplasticity mechanisms

Peripheral monocyte-derived cells counter amyloid plaque pathogenesis in a mouse model of Alzheimer’s disease

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Yan, Ping, Kim, Ki-Wook, Xiao, Qingli, Ma, Xiucui, Czerniewski, Leah R., Liu, Haiyan, Rawnsley, David R., Yan, Yan +4 more·2022·Journal of Clinical Investigation
DOI 10.1172/jci152565PMC PMC9151689
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Abstract

Microglia, the parenchymal tissue macrophages in the brain, surround amyloid plaques in brains of individuals with Alzheimer's disease (AD) but are ineffective at clearing amyloid to mitigate disease progression. Recent studies in mice indicate that microglia are derived exclusively from primitive yolk sac hematopoiesis and self-renew without contribution from ontogenically distinct monocytes/macrophages of definitive adult hematopoietic origin. Using a genetic fate-mapping approach to label cells of definitive hematopoietic origin throughout life span, we discovered that circulating monocytes contribute 6% of plaque-associated macrophages in aged AD mice. Moreover, peripheral monocytes contributed to a higher fraction of macrophages in the choroid plexus, meninges, and perivascular spaces of aged AD mice versus WT control mice, indicating enrichment at potential sites for entry into the brain parenchyma. Splenectomy, which markedly reduced circulating Ly6Chi monocytes, also reduced abundance of plaque-associated macrophages of definitive hematopoietic origin, resulting in increased amyloid plaque load. Together, these results indicate that peripherally derived monocytes invade the brain parenchyma, targeting amyloid plaques to reduce plaque load.

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  • A recent study reported a high frequency of monocyte-derived microglia in brains of octogenarians.

    “In line with this notion, a recent study reported a high frequency of MoMg in brains of octogenarians 28 , although the medical history of these individuals remains unknown.”

    From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [28]

    The Abstract (page unavailable) reports monocyte-derived cells among plaque-associated macrophages, but the finding is 6% in aged Alzheimer’s-model mice, not a high frequency in brains of human octogenarians. The Results (page unavailable) likewise describe mice aged at least 10 months; the cited paper does not report the claimed human observation. (LLM, conf=0.88)

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  • Available reports of monocyte-derived microglia in humans, as defined by CH mutations, refer to brain regions that overlap with areas in which monocyte-derived microglia accumulation is observed in aging mice, including occipital cortex, medulla and putamen.

    “Of note, the available reports of monocyte-derived microglia in humans, as defined by CH mutations, so far refer to brain regions that overlap with the areas in which we observe MoMg accumulation in the aging mice, including the occipital cortex, medulla and putamen 28,66 .”

    From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [28]

    Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

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  • Human monocyte-derived microglia were shown to harbor ATACseq signals in the Sall1 loci.

    “This is in line with recent data reported for human monocyte-derived microglia which were shown to harbor ATACseq signals in the Sall1 loci 28 .”

    From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [28]

    The Results describe marker expression in plaque-associated monocyte-derived cells in mice, and the Methods describe mouse fate-mapping experiments. Searches for Sall1, ATAC-seq, and chromatin accessibility found no passage reporting ATAC-seq signals at the Sall1 locus in human monocyte-derived microglia. (LLM, conf=0.76)

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  • The presence of CH mutations served as a proxy to identify HSC-derived cells among the brain MF compartment in the recent study by Jaiswal and colleagues.

    “The presence of CH mutations served also as a proxy to identify HSC-derived cells among the brain M F compartment in the recent study by Jaiswal and colleagues 28 .”

    From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [28]

    The Results describe using Flt3-Cre–driven GFP labeling to identify hematopoietic-lineage cells in mouse brain macrophage isolates. Our copy does not address the claimed use of clonal hematopoiesis (CH) mutations as a proxy in a study by Jaiswal and colleagues; searches for CH mutations, Jaiswal, and the proposed proxy found no supporting passage. The supplied passages have no page numbers. (LLM, conf=0.76)

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Cites

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Authors
Yan, P., Kim, K.-W., Xiao, Q., Ma, X., Czerniewski, L. R., Liu, H., Rawnsley, D. R., Yan, Y., Randolph, G. J., Epelman, S., Lee, J.-M., & Diwan, A.
Affiliations
  • Hope Center for Neurological Disorders (US)
  • Washington University in St. Louis (US)
  • University Health Network (CA)
Corresponding author
  • Epelman, Slava
  • Lee, Jin-Moo
  • Diwan, Abhinav
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2022-06-01
Volume
132
Issue
11
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci152565
PMC
PMC9151689
OpenAlex
W4229012234
Cited by
95
References
11
Citations by year
2026: 25 · 2025: 27 · 2024: 21 · 2023: 19 · 2022: 3
FWCI
6.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Clinical Investigation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Institute of Neurological Disorders and Stroke (R01NS094692, R21 NS082529)
  • Alzheimer’s Association (NIRG 12-242588)
  • The Heart and Stroke Foundation of Ontario (HSFO 7532)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126753)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
Alzheimer's disease, amyloid plaques, peripheral blood monocytes, microglia, yolk sac hematopoiesis, monocyte-derived macrophages, choroid plexus, meninges, perivascular spaces, splenectomy, Ly6Chi monocytes, fate mapping, mouse model
MeSH terms
Alzheimer Disease, Animals, Brain, Disease Models, Animal, Mice, Transgenic, Monocytes, Amyloid beta-Peptides, Microglia, Mice, Plaque, Amyloid

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