整合多组学揭示了家族性阿尔茨海默病中PSEN1、PSEN2和APP突变的常见内型。

Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer's disease.

作者信息

Valdes Phoebe, Caldwell Andrew B, Liu Qing, Fitzgerald Michael Q, Ramachandran Srinivasan, Karch Celeste M, Galasko Douglas R, Yuan Shauna H, Wagner Steven L, Subramaniam Shankar

机构信息

Department of Bioengineering, University of California, San Diego, La Jolla, CA, 92093, USA.

Bioengineering Graduate Program, University of California, San Diego, La Jolla, CA, 92093, USA.

出版信息

Alzheimers Res Ther. 2025 Jan 4;17(1):5. doi: 10.1186/s13195-024-01659-6.

BACKGROUND

PSEN1, PSEN2, and APP mutations cause Alzheimer's disease (AD) with an early age at onset (AAO) and progressive cognitive decline. PSEN1 mutations are more common and generally have an earlier AAO; however, certain PSEN1 mutations cause a later AAO, similar to those observed in PSEN2 and APP.

METHODS

We examined whether common disease endotypes exist across these mutations with a later AAO (~ 55 years) using hiPSC-derived neurons from familial Alzheimer's disease (FAD) patients harboring mutations in PSEN1, PSEN2, and APP and mechanistically characterized by integrating RNA-seq and ATAC-seq.

RESULTS

We identified common disease endotypes, such as dedifferentiation, dysregulation of synaptic signaling, repression of mitochondrial function and metabolism, and inflammation. We ascertained the master transcriptional regulators associated with these endotypes, including REST, ASCL1, and ZIC family members (activation), and NRF1 (repression).

CONCLUSIONS

FAD mutations share common regulatory changes within endotypes with varying severity, resulting in reversion to a less-differentiated state. The regulatory mechanisms described offer potential targets for therapeutic interventions.