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Early Alzheimer's disease pathology in human cortex involves transient cell states.
Gazestani, Vahid; Kamath, Tushar; Nadaf, Naeem M; Dougalis, Antonios; Burris, S J; Rooney, Brendan; Junkkari, Antti; Vanderburg, Charles; Pelkonen, Anssi; Gomez-Budia, Mireia; Välimäki, Nelli-Noora; Rauramaa, Tuomas; Therrien, Martine; Koivisto, Anne M; Tegtmeyer, Matthew; Herukka, Sanna-Kaisa; Abdulraouf, Abdulraouf; Marsh, Samuel E; Hiltunen, Mikko; Nehme, Ralda; Malm, Tarja; Stevens, Beth; Leinonen, Ville; Macosko, Evan Z.
Afiliación
  • Gazestani V; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Kamath T; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Graduate Program in Biophysics and Harvard/MIT MD-PhD Program, Harvard University, Cambridge, MA 02139, USA.
  • Nadaf NM; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Dougalis A; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
  • Burris SJ; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Rooney B; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
  • Junkkari A; Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland; Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland.
  • Vanderburg C; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Pelkonen A; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
  • Gomez-Budia M; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
  • Välimäki NN; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
  • Rauramaa T; Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland; Department of Pathology, Kuopio University Hospital, Kuopio, Finland.
  • Therrien M; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Koivisto AM; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland; Department of Neurosciences, University of Helsinki, Helsinki, Finland; Depart
  • Tegtmeyer M; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Herukka SK; Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
  • Abdulraouf A; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Marsh SE; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA.
  • Hiltunen M; Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
  • Nehme R; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Malm T; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
  • Stevens B; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute (HHMI), Boston, MA 02115, USA.
  • Leinonen V; Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland; Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland.
  • Macosko EZ; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Massachusetts General Hospital, Department of Psychiatry, Boston, MA 02114, USA. Electronic address: emacosko@broadinstitute.org.
Cell ; 186(20): 4438-4453.e23, 2023 09 28.
Article en En | MEDLINE | ID: mdl-37774681
ABSTRACT
Cellular perturbations underlying Alzheimer's disease (AD) are primarily studied in human postmortem samples and model organisms. Here, we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of AD pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes-which we refer to as the early cortical amyloid response-were prominent in neurons, wherein we identified a transitional hyperactive state preceding the loss of excitatory neurons, which we confirmed by acute slice physiology on independent biopsy specimens. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathology increased. Finally, both oligodendrocytes and pyramidal neurons upregulated genes associated with ß-amyloid production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Microglía / Enfermedad de Alzheimer / Lóbulo Frontal / Neuronas Límite: Humans Idioma: En Revista: Cell Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Microglía / Enfermedad de Alzheimer / Lóbulo Frontal / Neuronas Límite: Humans Idioma: En Revista: Cell Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos