Monocyte-derived Cells Invade Brain Parenchyma and Amyloid Plaques in Human Alzheimer’s Disease Hippocampus

Muñoz-Castro, Clara; Mejías Ortega, Marina; Sánchez Mejías, Elisabeth; Navarro Garrido, Victoria; Trujillo Estrada, Laura; Jiménez, Sebastián; García León, Juan Antonio; Fernández Valenzuela, Juan José; Sánchez Mico, María Virtudes; Romero Molina, Carmen; Moreno González, Inés; Baglietto Vargas, David; Vizuete Chacón, María Luisa; Gutiérrez, Antonia; Vitorica Ferrández, Francisco Javier

Monocyte-derived Cells Invade Brain Parenchyma and Amyloid Plaques in Human Alzheimer’s Disease Hippocampus

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...

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Autores:	Muñoz-Castro, Clara, Mejías Ortega, Marina, Sánchez Mejías, Elisabeth, Navarro Garrido, Victoria, Trujillo Estrada, Laura, Jiménez, Sebastián, García León, Juan Antonio, Fernández Valenzuela, Juan José, Sánchez Mico, María Virtudes, Romero Molina, Carmen, Moreno González, Inés, Baglietto Vargas, David, Vizuete Chacón, María Luisa, Gutiérrez, Antonia, Vitorica Ferrández, Francisco Javier
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2023
País:	España
Institución:	Universidad de Sevilla (US)
Repositorio:	idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:	oai:idus.us.es:11441/146554
Acceso en línea:	https://hdl.handle.net/11441/146554 https://doi.org/10.1186/s40478‑023‑01530‑z
Access Level:	acceso abierto
Palabra clave:	Alzheimer’s disease Amyloid plaques Brain infiltration Human hippocampus Microglia Myeloid cells

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spelling	Monocyte-derived Cells Invade Brain Parenchyma and Amyloid Plaques in Human Alzheimer’s Disease HippocampusMuñoz-Castro, ClaraMejías Ortega, MarinaSánchez Mejías, ElisabethNavarro Garrido, VictoriaTrujillo Estrada, LauraJiménez, SebastiánGarcía León, Juan AntonioFernández Valenzuela, Juan JoséSánchez Mico, María VirtudesRomero Molina, CarmenMoreno González, InésBaglietto Vargas, DavidVizuete Chacón, María LuisaGutiérrez, AntoniaVitorica Ferrández, Francisco JavierAlzheimer’s diseaseAmyloid plaquesBrain infiltrationHuman hippocampusMicrogliaMyeloid cellsMicroglia 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.European Commission. Fondo Europeo de Desarrollo Regional PI18/01556, PI21/00914, PI18/01557, PI21/00915Junta de Andalucía US-1262734, P20-00843, UMA18-FEDERJA-211, PI18-RT-2233Universidad de Málaga B-2019_06Ministerio de Ciencia, Innovación y Universidades RYC-2017-21879Springer NatureBioquímica y Biología MolecularEuropean Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)Junta de AndalucíaUniversidad de MálagaMinisterio de Ciencia, Innovación y Universidades (MICINN). España2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/146554https://doi.org/10.1186/s40478‑023‑01530‑zreponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésActa Neuropathologica Communications, 11 (1), 31.PI18/01556PI21/00914PI18/01557PI21/00915US-1262734P20-00843UMA18-FEDERJA-211PI18-RT-2233B-2019_06RYC-2017-21879https://doi.org/10.1186/s40478‑023‑01530‑zinfo:eu-repo/semantics/openAccessoai:idus.us.es:11441/1465542026-06-17T12:51:07Z
dc.title.none.fl_str_mv	Monocyte-derived Cells Invade Brain Parenchyma and Amyloid Plaques in Human Alzheimer’s Disease Hippocampus
title	Monocyte-derived Cells Invade Brain Parenchyma and Amyloid Plaques in Human Alzheimer’s Disease Hippocampus
spellingShingle	Monocyte-derived Cells Invade Brain Parenchyma and Amyloid Plaques in Human Alzheimer’s Disease Hippocampus Muñoz-Castro, Clara Alzheimer’s disease Amyloid plaques Brain infiltration Human hippocampus Microglia Myeloid cells
title_short	Monocyte-derived Cells Invade Brain Parenchyma and Amyloid Plaques in Human Alzheimer’s Disease Hippocampus
title_full	Monocyte-derived Cells Invade Brain Parenchyma and Amyloid Plaques in Human Alzheimer’s Disease Hippocampus
title_fullStr	Monocyte-derived Cells Invade Brain Parenchyma and Amyloid Plaques in Human Alzheimer’s Disease Hippocampus
title_full_unstemmed	Monocyte-derived Cells Invade Brain Parenchyma and Amyloid Plaques in Human Alzheimer’s Disease Hippocampus
title_sort	Monocyte-derived Cells Invade Brain Parenchyma and Amyloid Plaques in Human Alzheimer’s Disease Hippocampus
dc.creator.none.fl_str_mv	Muñoz-Castro, Clara Mejías Ortega, Marina Sánchez Mejías, Elisabeth Navarro Garrido, Victoria Trujillo Estrada, Laura Jiménez, Sebastián García León, Juan Antonio Fernández Valenzuela, Juan José Sánchez Mico, María Virtudes Romero Molina, Carmen Moreno González, Inés Baglietto Vargas, David Vizuete Chacón, María Luisa Gutiérrez, Antonia Vitorica Ferrández, Francisco Javier
author	Muñoz-Castro, Clara
author_facet	Muñoz-Castro, Clara Mejías Ortega, Marina Sánchez Mejías, Elisabeth Navarro Garrido, Victoria Trujillo Estrada, Laura Jiménez, Sebastián García León, Juan Antonio Fernández Valenzuela, Juan José Sánchez Mico, María Virtudes Romero Molina, Carmen Moreno González, Inés Baglietto Vargas, David Vizuete Chacón, María Luisa Gutiérrez, Antonia Vitorica Ferrández, Francisco Javier
author_role	author
author2	Mejías Ortega, Marina Sánchez Mejías, Elisabeth Navarro Garrido, Victoria Trujillo Estrada, Laura Jiménez, Sebastián García León, Juan Antonio Fernández Valenzuela, Juan José Sánchez Mico, María Virtudes Romero Molina, Carmen Moreno González, Inés Baglietto Vargas, David Vizuete Chacón, María Luisa Gutiérrez, Antonia Vitorica Ferrández, Francisco Javier
author2_role	author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Bioquímica y Biología Molecular European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER) Junta de Andalucía Universidad de Málaga Ministerio de Ciencia, Innovación y Universidades (MICINN). España
dc.subject.none.fl_str_mv	Alzheimer’s disease Amyloid plaques Brain infiltration Human hippocampus Microglia Myeloid cells
topic	Alzheimer’s disease Amyloid plaques Brain infiltration Human hippocampus Microglia Myeloid cells
description	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.
publishDate	2023
dc.date.none.fl_str_mv	2023
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	https://hdl.handle.net/11441/146554 https://doi.org/10.1186/s40478‑023‑01530‑z
url	https://hdl.handle.net/11441/146554 https://doi.org/10.1186/s40478‑023‑01530‑z
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	Acta Neuropathologica Communications, 11 (1), 31. PI18/01556 PI21/00914 PI18/01557 PI21/00915 US-1262734 P20-00843 UMA18-FEDERJA-211 PI18-RT-2233 B-2019_06 RYC-2017-21879 https://doi.org/10.1186/s40478‑023‑01530‑z
dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf application/pdf
dc.publisher.none.fl_str_mv	Springer Nature
publisher.none.fl_str_mv	Springer Nature
dc.source.none.fl_str_mv	reponame:idUS. Depósito de Investigación de la Universidad de Sevilla instname:Universidad de Sevilla (US)
instname_str	Universidad de Sevilla (US)
reponame_str	idUS. Depósito de Investigación de la Universidad de Sevilla
collection	idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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Monocyte-derived Cells Invade Brain Parenchyma and Amyloid Plaques in Human Alzheimer’s Disease Hippocampus

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