Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology
Why is this work in the frame?
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
No Canadian affiliation. An affiliation-only frame — the usual design — would never have seen this work. It is one of the works that make the case for inverting the frame.
The three-model screen
all 1,000 screened works →All three models called this out of scope.
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.
Abstract
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.
Stored with the screening record, where it is evidence for the labels above.
The record
- Venue
- EMBO Molecular Medicine
- Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Field
- Neuroscience
- Canadian institutions
- —
- Funders
- 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
- Keywords
- MicrogliaPathologyAmyloid (mycology)Tau pathologyAmyloid βMedicineGeneAlzheimer's diseaseBiologyNeuroscienceDiseaseInflammationImmunologyGenetics
- Has abstract in OpenAlex
- yes