Scientists reveal how brain cells in Alzheimer's go awry, lo
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Despite the prevalence of Alzheimer's, there are still no treatments, in part because it has been challenging to study how the disease develops. Now, scientists have uncovered new insights into what goes awry during Alzheimer's by growing neurons that resemble—more accurately than ever before—brain cells in older patients. And like patients themselves, the afflicted neurons appear to lose their cellular identity.

Sporadic Alzheimer’s disease (AD) exclusively affects elderly people. Using direct conversion of AD patient fibroblasts into induced neurons (iNs), scientists 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, they 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.

The findings identify AD-related neuronal changes as age-dependent cellular programs that impair neuronal identity.

Cell Stem Cell