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In vivo validation of late-onset Alzheimer's disease genetic risk factors.
Sasner, Michael; Preuss, Christoph; Pandey, Ravi S; Uyar, Asli; Garceau, Dylan; Kotredes, Kevin P; Williams, Harriet; Oblak, Adrian L; Lin, Peter Bor-Chian; Perkins, Bridget; Soni, Disha; Ingraham, Cindy; Lee-Gosselin, Audrey; Lamb, Bruce T; Howell, Gareth R; Carter, Gregory W.
Afiliación
  • Sasner M; The Jackson Laboratory, Bar Harbor, Maine, USA.
  • Preuss C; The Jackson Laboratory, Bar Harbor, Maine, USA.
  • Pandey RS; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.
  • Uyar A; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.
  • Garceau D; The Jackson Laboratory, Bar Harbor, Maine, USA.
  • Kotredes KP; The Jackson Laboratory, Bar Harbor, Maine, USA.
  • Williams H; The Jackson Laboratory, Bar Harbor, Maine, USA.
  • Oblak AL; Stark Neurosciences Research Institute, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
  • Lin PB; Stark Neurosciences Research Institute, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
  • Perkins B; Stark Neurosciences Research Institute, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
  • Soni D; Stark Neurosciences Research Institute, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
  • Ingraham C; Stark Neurosciences Research Institute, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
  • Lee-Gosselin A; Stark Neurosciences Research Institute, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
  • Lamb BT; Stark Neurosciences Research Institute, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
  • Howell GR; The Jackson Laboratory, Bar Harbor, Maine, USA.
  • Carter GW; The Jackson Laboratory, Bar Harbor, Maine, USA.
Alzheimers Dement ; 20(7): 4970-4984, 2024 07.
Article en En | MEDLINE | ID: mdl-38687251
ABSTRACT

INTRODUCTION:

Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action.

METHODS:

Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE ε4/ε4 and Trem2*R47H. The potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts.

RESULTS:

We created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes.

DISCUSSION:

These results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics. HIGHLIGHTS A novel approach to validate genetic risk factors for late-onset AD (LOAD) is presented. LOAD risk variants were knocked in to conserved mouse loci. Variant effects were assayed by transcriptional analysis. Risk variants in Abca7, Mthfr, Plcg2, and Sorl1 loci modeled molecular signatures of clinical disease. This approach should generate more translationally relevant animal models.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ratones Transgénicos / Predisposición Genética a la Enfermedad / Modelos Animales de Enfermedad / Enfermedad de Alzheimer Límite: Animals / Female / Humans / Male Idioma: En Revista: Alzheimers Dement Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ratones Transgénicos / Predisposición Genética a la Enfermedad / Modelos Animales de Enfermedad / Enfermedad de Alzheimer Límite: Animals / Female / Humans / Male Idioma: En Revista: Alzheimers Dement Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos