Dedifferentiation and neuronal repression define familial Alzheimer’s disease

Abstract

Identifying the systems-level mechanisms that lead to Alzheimer’s disease, an unmet need, is an essential step toward the development of therapeutics. In this work, we report that the key disease-causative mechanisms, including dedifferentiation and repression of neuronal identity, are triggered by changes in chromatin topology. Here, we generated human induced pluripotent stem cell (hiPSC)–derived neurons from donor patients with early-onset familial Alzheimer’s disease (EOFAD) and used a multiomics approach to mechanistically characterize the modulation of disease-associated gene regulatory programs. We demonstrate that EOFAD neurons dedifferentiate to a precursor-like state with signatures of ectoderm and nonectoderm lineages. RNA-seq, ATAC-seq, and ChIP-seq analysis reveals that transcriptional alterations in the cellular state are orchestrated by changes in histone methylation and chromatin topology. Furthermore, we demonstrate that these mechanisms are observed in EOFAD-patient brains, validating our hiPSC-derived neuron models. The mechanistic endotypes of Alzheimer’s disease uncovered here offer key insights for therapeutic interventions.

Progressive Brain Degeneration From Subjective Cognitive Decline to Amnestic Mild Cognitive Impairment: Evidence From Large-Scale Anatomical Connection Classification Analysis

“…We speculate that perhaps the region is undergoing a transition from a cost-effective network to a random network during the SCD stage and that some unnecessary connections to this brain region may cause interference with memory function. This is consistent with the phenomenon of brain dedifferentiation in aging and disease development ( Goh, 2011 ; Caldwell et al, 2020 ). This is still only our conjecture, and follow-up studies need more experimental evidence to further validate it.…”

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

“…Cellular aging features ( Huh et al., 2016 ; Mertens et al., 2015a , 2018 ; Tang et al., 2017 ; Victor et al., 2014 ) and adult-like neuronal identity of iNs ( Luo et al., 2019 ) are likely critical for the emergence of such phenotypes in sporadic AD neurons, because erasure of aging signatures and re-gaining of fetal identity represents a potent rescue in this study ( Miller et al., 2013 ; Ocampo et al., 2016 ). However, neurons that carry aggressive familial AD mutations still show a similar phenotype when generated from iPSCs ( Caldwell et al., 2020 ). Collectively, for studying age-related vulnerability and mechanisms relevant to AD, iNs have advantages over iPSC models and thus complement isogenic iPSC strategies ( van der Kant et al., 2019 ; Meyer et al., 2019 ; Woodruff et al., 2013 ).…”

E2F4 as a single multifactorial target against Alzheimer’s disease

“…A recent study has proposed E2F4 as a major regulator of most AD-specific gene networks ( 15 ), and other bioinformatics-based studies suggest that E2F4 participates in this disease ( 16-18 ). Moreover, distinct AD-related genes contain E2F transcription factor binding sites ( 19 ), and a genome-wide association study for late onset AD has identified a single nucleotide polymorphism that modifies a DNA binding motif of E2F4 as relevant for the disease ( 20 ).…”