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Alzheimer risk-increasing TREM2 variant causes aberrant cortical synapse density and promotes network hyperexcitability in mouse models.
Das, Melanie; Mao, Wenjie; Voskobiynyk, Yuliya; Necula, Deanna; Lew, Irene; Petersen, Cathrine; Zahn, Allie; Yu, Gui-Qiu; Yu, Xinxing; Smith, Nicholas; Sayed, Faten A; Gan, Li; Paz, Jeanne T; Mucke, Lennart.
Afiliación
  • Das M; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Mao W; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Voskobiynyk Y; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Necula D; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, CA 94158, USA.
  • Lew I; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Petersen C; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, CA 94158, USA.
  • Zahn A; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Yu GQ; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Yu X; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Smith N; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Sayed FA; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Gan L; Helen and Robert Appel Alzheimer's Disease Research Institute, Weill Cornell Medicine, New York City, NY 10065, USA.
  • Paz JT; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, CA 94158, USA; Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, CA 94158, US
  • Mucke L; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, CA 94158, USA; Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, CA 94158, US
Neurobiol Dis ; 186: 106263, 2023 10 01.
Article en En | MEDLINE | ID: mdl-37591465
The R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2) increases the risk of Alzheimer's disease (AD). To investigate potential mechanisms, we analyzed knockin mice expressing human TREM2-R47H from one mutant mouse Trem2 allele. TREM2-R47H mice showed increased seizure activity in response to an acute excitotoxin challenge, compared to wildtype controls or knockin mice expressing the common variant of human TREM2. TREM2-R47H also increased spontaneous thalamocortical epileptiform activity in App knockin mice expressing amyloid precursor proteins bearing autosomal dominant AD mutations and a humanized amyloid-ß sequence. In mice with or without such App modifications, TREM2-R47H increased the density of putative synapses in cortical regions without amyloid plaques. TREM2-R47H did not affect synaptic density in hippocampal regions with or without plaques. We conclude that TREM2-R47H increases AD-related network hyperexcitability and that it may do so, at least in part, by causing an imbalance in synaptic densities across brain regions.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Alzheimer Tipo de estudio: Etiology_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Neurobiol Dis Asunto de la revista: NEUROLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Alzheimer Tipo de estudio: Etiology_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Neurobiol Dis Asunto de la revista: NEUROLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos