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

Mertens, Jérôme; Herdy, Joseph R.; Traxler, Larissa; Schäfer, Simon; Schlachetzki, J; Böhnke, Lena; Reid, Dylan A.; Lee, Hyungjun; Zangwill, Dina; Fernandes, Diana Pereira; Agarwal, R. K.; Lucciola, Raffaella; Zhou-Yang, Lucia; Karbacher, Lukas; Edenhofer, Frank; Stern, Shani; Horvath, Steve; Paquola, Apuã C.M.; Glass, Christopher K.; Yuan, Shauna H.; Ku, Manching; Szűcs, Attila; Goldstein, Lawrence S.B.; Galasko, Douglas; Gage, Fred H.

doi:10.1016/j.stem.2021.04.004

Cited by 130 publications

(98 citation statements)

References 106 publications

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“…The second refers to neurons with AD phenotype, whose profound chromatin, nuclear, somatodendritic, and axonal transformation materialize the characteristic AD neurodegeneration [ 79 , 175 ]. Recent works in induced neurons from patient-derived fibroblasts have linked oxidative stress and DNA damage to aberrant cell cycle re-entry, apoptosis activation, and, importantly, the loss of a differentiation state and a “return to immaturity” [ 176 , 177 ]. The RNA-seq analysis of 82 temporal cortex neurons from a late AD sample identified the up-regulation of 600 genes related to epithelial–mesenchymal transition and cancer along with the downregulation of genes associated with mature neuronal identity [ 171 ].…”

Section: Different Chromatin Landscapes Associated To Early and Late Ad Stagesmentioning

confidence: 99%

Phospho-Tau and Chromatin Landscapes in Early and Late Alzheimer’s Disease

Gil

Niño

Guerrero

et al. 2021

IJMS

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Cellular identity is determined through complex patterns of gene expression. Chromatin, the dynamic structure containing genetic information, is regulated through epigenetic modulators, mainly by the histone code. One of the main challenges for the cell is maintaining functionality and identity, despite the accumulation of DNA damage throughout the aging process. Replicative cells can remain in a senescent state or develop a malign cancer phenotype. In contrast, post-mitotic cells such as pyramidal neurons maintain extraordinary functionality despite advanced age, but they lose their identity. This review focuses on tau, a protein that protects DNA, organizes chromatin, and plays a crucial role in genomic stability. In contrast, tau cytosolic aggregates are considered hallmarks of Alzheimer´s disease (AD) and other neurodegenerative disorders called tauopathies. Here, we explain AD as a phenomenon of chromatin dysregulation directly involving the epigenetic histone code and a progressive destabilization of the tau–chromatin interaction, leading to the consequent dysregulation of gene expression. Although this destabilization could be lethal for post-mitotic neurons, tau protein mediates profound cellular transformations that allow for their temporal survival.

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Section: Different Chromatin Landscapes Associated To Early and Late Ad Stagesmentioning

confidence: 99%

Phospho-Tau and Chromatin Landscapes in Early and Late Alzheimer’s Disease

Gil

Niño

Guerrero

et al. 2021

IJMS

View full text Add to dashboard Cite

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“…Recent studies of neurons from subjects with familial and sporadic AD indicate that developmental processes are also consistently perturbed. Evidence from induced pluripotent stem cell-derived neurons from AD subjects indicates that diseased nerve cells develop features of de-differentiation reminiscent of a progenitor-like fate; they show reactivation of a cell-cycle phenotype, and they lack the resiliency of mature neurons (reviewed in Mertens et al, 2021 ). Collectively, recent studies of progressive neurodegenerative disorders suggest that genomic instability (i.e., mutations) during early brain development contributes to the pathogenesis of adult-onset neurodegeneration.…”

Section: Developmental Origins Of Neurodegenerative Diseasementioning

confidence: 99%

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

Kisby

Spencer

2021

Front. Neurosci.

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Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC) is a disappearing prototypical neurodegenerative disorder (tau-dominated polyproteinopathy) linked with prior exposure to phytogenotoxins in cycad seed used for medicine and/or food. The principal cycad genotoxin, methylazoxymethanol (MAM), forms reactive carbon-centered ions that alkylate nucleic acids in fetal rodent brain and, depending on the timing of systemic administration, induces persistent developmental abnormalities of the cortex, hippocampus, cerebellum, and retina. Whereas administration of MAM prenatally or postnatally can produce animal models of epilepsy, schizophrenia or ataxia, administration to adult animals produces little effect on brain structure or function. The neurotoxic effects of MAM administered to rats during cortical brain development (specifically, gestation day 17) are used to model the histological, neurophysiological and behavioral deficits of human schizophrenia, a condition that may precede or follow clinical onset of motor neuron disease in subjects with sporadic ALS and ALS/PDC. While studies of migrants to and from communities impacted by ALS/PDC indicate the degenerative brain disorder may be acquired in juvenile and adult life, a proportion of indigenous cases shows neurodevelopmental aberrations in the cerebellum and retina consistent with MAM exposure in utero. MAM induces specific patterns of DNA damage and repair that associate with increased tau expression in primary rat neuronal cultures and with brain transcriptional changes that parallel those associated with human ALS and Alzheimer’s disease. We examine MAM in relation to neurodevelopment, epigenetic modification, DNA damage/replicative stress, genomic instability, somatic mutation, cell-cycle reentry and cellular senescence. Since the majority of neurodegenerative disease lacks a solely inherited genetic basis, research is needed to explore the hypothesis that early-life exposure to genotoxic agents may trigger or promote molecular events that culminate in neurodegeneration.

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“…Directly induced neurons (iNs) obtained from the fibroblasts preserved the aging status of the donors, while the aging status of the donor was erased in iPSCs. The iNs of sporadic AD patients could also reflect AD phenotypes, such as uncomplicated dendrites, reduced synapses, epigenetic erosion, and increased DNA damage ( Mertens et al, 2021 ). Thus, AD models of iN cells can also be used to evaluate aging-dependent sex effects and could provide insights into sex and age-related changes in AD.…”

Section: Next Generation In Vitro Models Of Ad and Future Utilization For The Study Of Sex Differencementioning

confidence: 99%

Utilization of Human Induced Pluripotent Stem Cells-Derived In vitro Models for the Future Study of Sex Differences in Alzheimer’s Disease

Supakul

Okano

Maeda

2021

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is an aging-dependent neurodegenerative disease that impairs cognitive function. Although the main pathologies of AD are the aggregation of amyloid-beta (Aβ) and phosphorylated Tau protein, the mechanisms that lead to these pathologies and their effects are believed to be heterogeneous among patients. Many epidemiological studies have suggested that sex is involved in disease prevalence and progression. The reduction of sex hormones contributes to the pathogenesis of AD, especially in females, suggesting that the supplementation of sex hormones could be a therapeutic intervention for AD. However, interventional studies have revealed that hormone therapy is beneficial under limited conditions in certain populations with specific administration methods. Thus, this suggests the importance of identifying crucial factors that determine hormonal effects in patients with AD. Based on these factors, it is necessary to decide which patients will receive the intervention before starting it. However, the long observational period and many uncontrollable environmental factors in clinical trials made it difficult to identify such factors, except for the APOE ε4 allele. Induced pluripotent stem cells (iPSCs) derived from patients can differentiate into neurons and recapitulate some aspects of AD pathogenesis. This in vitro model allows us to control non-cell autonomous factors, including the amount of Aβ aggregates and sex hormones. Hence, iPSCs provide opportunities to investigate sex-dependent pathogenesis and predict a suitable population for clinical trials of hormone treatment.

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

Cited by 130 publications

References 106 publications

Phospho-Tau and Chromatin Landscapes in Early and Late Alzheimer’s Disease

Phospho-Tau and Chromatin Landscapes in Early and Late Alzheimer’s Disease

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

Utilization of Human Induced Pluripotent Stem Cells-Derived In vitro Models for the Future Study of Sex Differences in Alzheimer’s Disease

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