Monocyte-derived cells invade brain parenchyma and amyloid plaques in human Alzheimer’s disease hippocampus
Open accessAbstract
Microglia are brain-resident myeloid cells and play a major role in the innate immune responses of the CNS and the pathogenesis of Alzheimer's disease (AD). However, the contribution of nonparenchymal or brain-infiltrated myeloid cells to disease progression remains to be demonstrated. Here, we show that monocyte-derived cells (MDC) invade brain parenchyma in advanced stages of AD continuum using transcriptional analysis and immunohistochemical characterization in post-mortem human hippocampus. Our findings demonstrated that a high proportion (60%) of demented Braak V–VI individuals was associated with up-regulation of genes rarely expressed by microglial cells and abundant in monocytes, among which stands the membrane-bound scavenger receptor for haptoglobin/hemoglobin complexes or Cd163. These Cd163-positive MDC invaded the hippocampal parenchyma, acquired a microglial-like morphology, and were located in close proximity to blood vessels. Moreover, and most interesting, these invading monocytes infiltrated the nearby amyloid plaques contributing to plaque-associated myeloid cell heterogeneity. However, in aged-matched control individuals with hippocampal amyloid pathology, no signs of MDC brain infiltration or plaque invasion were found. The previously reported microglial degeneration/dysfunction in AD hippocampus could be a key pathological factor inducing MDC recruitment. Our data suggest a clear association between MDC infiltration and endothelial activation which in turn may contribute to damage of the blood brain barrier integrity. The recruitment of monocytes could be a consequence rather than the cause of the severity of the disease. Whether monocyte infiltration is beneficial or detrimental to AD pathology remains to be fully elucidated. These findings open the opportunity to design targeted therapies, not only for microglia but also for the peripheral immune cell population to modulate amyloid pathology and provide a better understanding of the immunological mechanisms underlying the progression of AD.
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Postmortem AD brain tissues show extensive monocyte infiltration into the brain parenchyma, where monocytes cluster around amyloid-β plaques.
“End point analyses of postmortem AD brain tissues show extensive monocyte infiltration into the brain parenchyma of patients with AD, where they cluster around amyloid-β (Aβ) plaques (13, 14).”
From Understanding monocyte-driven neuroinflammation in Alzheimer’s disease using human cortical organoid microphysiological systems (2025) · cites this paper as [13]
The Discussion (page not provided) reports monocyte infiltration into AD hippocampal parenchyma and an association of CD163-positive cells with amyloid-β plaques. It does not support describing infiltration as extensive across AD brains: the authors call the population small, report substantial variation between patients, and note that some AD cases had little or no infiltration. (LLM, conf=0.90)
Experimental — accuracy not yet measuredActivated microglia and infiltrating monocytes are detectable in the early stages of AD.
“Given that activated microglia and infiltrating monocytes are detectable in the early stages of AD [27], basal over-activation of innate immune cells in females could be a potential link to the increased prevalence of AD in women.”
From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [27]
The Results section on parenchymal and plaque-associated CD163 cells reports activated microglia at plaques in early Braak II cases, but no infiltrating CD163-positive cells in those cases’ hippocampal parenchyma. The Discussion notes high monocyte-infiltration levels in some non-demented Braak II or III–IV cases, while saying infiltration was predominantly found in advanced AD and might reflect other comorbidities. The source therefore does not support presenting both cell populations as generally detectable in early AD. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAD monocytes colocalize with Aβ in hCO-MPSs.
“AD monocytes also colocalized with Aβ in the hCO-MPSs (Fig. 2C), supporting the previous observations that infiltrated monocytes accumulate around Aβ plaques in the brain tissues of patients with AD (13).”
From Understanding monocyte-driven neuroinflammation in Alzheimer’s disease using human cortical organoid microphysiological systems (2025) · cites this paper as [13]
The population of infiltrated monocytes increases as AD progression worsens.
“The population of infiltrated monocytes was also found to increase as the AD progression worsens (13).”
From Understanding monocyte-driven neuroinflammation in Alzheimer’s disease using human cortical organoid microphysiological systems (2025) · cites this paper as [13]
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“The population of infiltrated monocytes was also found to increase as the AD progression worsens ( 13 ).”
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“Given that activated microglia and infiltrating monocytes are detectable in the early stages of AD [27], basal over-activation of innate immune cells in females could be a potential link to the increased prevalence of AD in women.”
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Targeting Microglial Activation to Modulate Neuroinflammation in Alzheimer’s Disease
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Trained immunity in acute and chronic neurological diseases
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Rationale and emerging evidence for microglial replacement in Alzheimer’s disease
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TAMing Gliomas: Unraveling the Roles of Iba1 and CD163 in Glioblastoma
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Skeleton keys and Trojan horses: a review of therapeutic delivery to the brain
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Aging and neurodegeneration: when systemic dysregulations affect brain macrophage heterogeneity
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Role of non-neuronal cells in neurorepair: a focus on proteinopathy and neurodegeneration
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Natural Killer Cells in Alzheimer's Disease: From Foe to Friend
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Alzheimer’s disease causes bone marrow myelopoiesis dysfunctionPreprint
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Intravital observation of neuronal and immune cell dynamics in the developing mammalian brain
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- Authors
- Muñoz-Castro, C., Mejias-Ortega, M., Sanchez-Mejias, E., Navarro, V., Trujillo-Estrada, L., Jimenez, S., Garcia-Leon, J. A., Fernandez-Valenzuela, J. J., Sanchez-Mico, M. V., Romero-Molina, C., Moreno-Gonzalez, I., Baglietto-Vargas, D., Vizuete, M., Gutierrez, A., & Vitorica, J.
- Affiliations
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Venue
- Acta Neuropathologica Communications
- Published
- 2023-02-28
- Volume
- 11
- Issue
- 1
- Pages
- 31-31
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC9976401
- OpenAlex
- W4322621114
- Cited by
- 66
- References
- 68
- Citations by year
- 2026: 19 · 2025: 25 · 2024: 17 · 2023: 5
- FWCI
- 6.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- Repositorio Institucional de la Universidad de Málaga (University of Málaga) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Deposito de Investigacion Universidad de Sevilla (University of Seville) (submittedVersion, cc-by-nc-nd)
- Funders
- Instituto de Salud Carlos III (PI18/01556, PI21/00914, PI18/01557, PI21/00915)
- Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (US-1262734)
- Consejería de Economía, Conocimiento, Empresas y Universidad, Junta de Andalucía (P20-00843, UMA18-FEDERJA-211, PI18-RT-2233)
- Ministerio de Ciencia, Innovación y Universidades (PID2019-108911RA-100, PID2019-107090RA-I00)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- Alzheimer's disease, monocyte-derived cells, microglia, hippocampus, amyloid plaques, CD163, endothelial activation, blood-brain barrier, myeloid cell heterogeneity, Braak stages, postmortem brain
- MeSH terms
- Aged, Alzheimer Disease, Brain, Hippocampus, Humans, Monocytes, Plaque, Amyloid, Amyloidogenic Proteins
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.
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