Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology
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Mouse-model transcriptomics of Alzheimer risk genes and microglial response; the object is disease biology.
The study investigates Alzheimer disease biology and genetic risk mechanisms, not research practice.
Biomedical genetics of Alzheimer risk genes and microglial response to pathology.
Résumé
Abstract Polygenic risk scores have identified that genetic variants without genome‐wide significance still add to the genetic risk of developing Alzheimer's disease (AD). Whether and how subthreshold risk loci translate into relevant disease pathways is unknown. We investigate here the involvement of AD risk variants in the transcriptional responses of two mouse models: APPswe/PS1 L166P and Thy‐TAU22. A unique gene expression module, highly enriched for AD risk genes, is specifically responsive to Aβ but not TAU pathology. We identify in this module 7 established AD risk genes ( APOE , CLU , INPP5D , CD33, PLCG2 , SPI1, and FCER1G ) and 11 AD GWAS genes below the genome‐wide significance threshold ( GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN, and BLNK), that become significantly upregulated when exposed to Aβ. Single microglia sequencing confirms that Aβ, not TAU, pathology induces marked transcriptional changes in microglia, including increased proportions of activated microglia. We conclude that genetic risk of AD functionally translates into different microglia pathway responses to Aβ pathology, placing AD genetic risk downstream of the amyloid pathway but upstream of TAU pathology.
Conservé avec la notice de tri, où il sert de preuve aux étiquettes ci-dessus.
La notice
- Revue
- EMBO Molecular Medicine
- Thématique
- Neuroinflammation and Neurodegeneration Mechanisms
- Domaine
- Neuroscience
- Établissements canadiens
- —
- Organismes subventionnaires
- Fondation pour la Recherche sur AlzheimerVlaams Instituut voor BiotechnologieFonds Wetenschappelijk OnderzoekVlaamse regeringVlaamse OverheidKU LeuvenAlzheimer SocietyAgence Nationale de la RechercheUK Research and InnovationMedical Research CouncilAlzheimer's Association
- Mots-clés
- MicrogliaPathologyAmyloid (mycology)Tau pathologyAmyloid βMedicineGeneAlzheimer's diseaseBiologyNeuroscienceDiseaseInflammationImmunologyGenetics
- Résumé présent dans OpenAlex
- oui