Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer's patients

מאת: Mertens J., Herdy J.R., Traxler L., Schafer S.T., Schlachetzki J.C.M., Böhnke L., Reid D.A., Lee H., Zangwill D., Fernandes D.P., Agarwal R.K., Lucciola R., Zhou-Yang L., Karbacher L., Edenhofer F., Stern S., Horvath S., Paquola A.C.M., Glass C.K., Yuan S.H., Ku M., Szücs A., Goldstein L.S.B., Galasko D., Gage F.H.
פורסם ב: Cell Stem Cell
תיאור: Sporadic Alzheimer's disease (AD) exclusively affects elderly people. Using direct conversion of AD patient fibroblastsinto induced neurons (iNs), we generated an age-equivalent neuronal model. AD patient-derived iNs exhibit strong neuronal transcriptome signatures characterized by downregulation of mature neuronal properties and upregulation of immature and progenitor-like signaling pathways. Mapping iNs to longitudinal neuronal differentiation trajectory data demonstrated that AD iNs reflect a hypo-mature neuronal identity characterized by markers of stress, cell cycle, and de-differentiation. Epigenetic landscape profiling revealed an underlying aberrant neuronal state that shares similarities with malignant transformation and age-dependent epigenetic erosion. To probe for the involvement of aging, we generated rejuvenated iPSC-derived neurons that showed no significant disease-related transcriptome signatures, a feature that is consistent with epigenetic clock and brain ontogenesis mapping, which indicate that fibroblast-derived iNs more closely reflect old adult brain stages. Our findings identify AD-related neuronal changes as age-dependent cellular programs that impair neuronal identity. © 2021 The Author(s)
SDGs : SDG 03  |  יחידות: מדעי הטבע  | מועד: 2021 |  קישור