Human iPSC-Derived Neurons as A Platform for Deciphering the Mechanisms behind Brain Aging

Chao, Chuan-Chuan; Shen, Po-Wen; Tzeng, Tsai-Yu; Kung, Hsing-Jien; Tsai, Ting‐Fen; Wong, Yu Hui

doi:10.3390/biomedicines9111635

Cited by 8 publications

(3 citation statements)

References 325 publications

(335 reference statements)

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“…While our five kinases have been implicated in traditional AD pathology (such as tau phosphorylation, amyloid processing), there is emerging evidence for a role in mediating key metabolic pathways. In fact, the three shared pathways in the underrepresented kinases converge on classical pathways mediating metabolic pathways: FoxO, Prolactin, and Cellular senescence (41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

Alterations in protein kinase networks in astrocytes and neurons derived from patients with familial Alzheimer’s Disease

Henkel

Joyce

Shedroff

et al. 2022

Preprint

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Neurons and astrocytes derived from Alzheimers Disease (AD) patient induced pluripotent stem cells are an evolving technology used to study the pathogenesis and etiology of AD. As the utility of mouse models of AD are increasingly coming into questions, using iPSC technology may offer an opportunity to study this disease with human substrates. Herein, we using a hypothesis generating platform, the PamGene12 Kinome Array, to identify core protein kinases in neurons and astrocytes derived from familial AD patient iPSCs. We identified five core protein kinases in these cells and examined the pathways in which they are enriched. Importantly, we complement our findings using an in-silico approach with postmortem AD brain datasets. While these protein kinases have been conceptualized in the context of traditional AD pathology, they have not been explored in the context of aberrant signaling in the pathophysiology of the disease.

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Section: Discussionmentioning

confidence: 99%

Alterations in protein kinase networks in astrocytes and neurons derived from patients with familial Alzheimer’s Disease

Henkel

Joyce

Shedroff

et al. 2022

Preprint

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“…Moreover, studies demonstrated that in many cases iPSC-derived disease models don’t exhibit disease-associated phenotypes under normal culture condition ( Dimos et al, 2008 ; Soldner et al, 2009 ; Zhang et al, 2010 ; HD iPSC Consortium, 2012 ) only upon introducing interventions to mimic aging-like phenotype (ROS, telomere manipulation, progerin, etc.) ( HD iPSC Consortium, 2012 ; Miller et al, 2013 ; Vera et al, 2016 ; Wu et al, 2019 ; Chao et al, 2021 ).…”

Section: Cellular Reprogramming Models To Study Autophagymentioning

confidence: 99%

Fountain of youth—Targeting autophagy in aging

Danics

Abbas

Kis

et al. 2023

Front. Aging Neurosci.

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As our society ages inexorably, geroscience and research focusing on healthy aging is becoming increasingly urgent. Macroautophagy (referred to as autophagy), a highly conserved process of cellular clearance and rejuvenation has attracted much attention due to its universal role in organismal life and death. Growing evidence points to autophagy process as being one of the key players in the determination of lifespan and health. Autophagy inducing interventions show significant improvement in organismal lifespan demonstrated in several experimental models. In line with this, preclinical models of age-related neurodegenerative diseases demonstrate pathology modulating effect of autophagy induction, implicating its potential to treat such disorders. In humans this specific process seems to be more complex. Recent clinical trials of drugs targeting autophagy point out some beneficial effects for clinical use, although with limited effectiveness, while others fail to show any significant improvement. We propose that using more human-relevant preclinical models for testing drug efficacy would significantly improve clinical trial outcomes. Lastly, the review discusses the available cellular reprogramming techniques used to model neuronal autophagy and neurodegeneration while exploring the existing evidence of autophagy’s role in aging and pathogenesis in human-derived in vitro models such as embryonic stem cells (ESCs), induced pluripotent stem cell derived neurons (iPSC-neurons) or induced neurons (iNs).

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“…Although more protocols are available for generating iPSCsNs than directly converted neurons, both model systems have advantages and limitations. As a scientist, research budgets are often limited, making time and money crucial when choosing in vitro models for investigation [25, 26]. Moreover, a model system that yields a high number of cells is preferable.…”

Section: Introductionmentioning

confidence: 99%

Preservation of an Aging-Associated Mitochondrial Signature in Advanced Human Neuronal Models

Varghese,

Szabo,

Cader

et al. 2024

Preprint

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This study investigated whether induced pluripotent stem cell-derived neurons (iPSCsNs) and directly converted neurons (iNs) generated from the same cells of origin (human fibroblasts) represent aging-related characteristics on mitochondrial levels. There is still uncertainty regarding the potential for rejuvenation or preservation of an aging-associated donor signature in aged iPSCsNs upon transition through pluripotent states, while direct conversion retains the aging-associated mitochondrial impairments. Surprisingly, both aged neuronal models exhibited age-associated donor phenotypes, including decreased ATP, mitochondrial membrane potential, mitochondrial respiration, NAD+/NADH ratio, and increased radical levels and mitochondrial mass. Besides, a fragmented mitochondrial network was observed in both aged neuronal models. However, unlike aged iNs, aged iPSCsNs did not show a metabolic shift towards anaerobic glycolysis to compensate for the energy deficit. Moreover, the mRNA expression profile significantly differed between aged iPSCsNs and aged iNs. Our study indicates that aged iPSCsNs may experience rejuvenation in certain parameters, such as transcriptomics and the aging-associated glycolytic shift. Nevertheless, aged iPSCsNs can be a valuable tool for studying neuronal aging of mitochondrial parameters in vitro alongside aged iNs.

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Human iPSC-Derived Neurons as A Platform for Deciphering the Mechanisms behind Brain Aging

Cited by 8 publications

References 325 publications

Alterations in protein kinase networks in astrocytes and neurons derived from patients with familial Alzheimer’s Disease

Alterations in protein kinase networks in astrocytes and neurons derived from patients with familial Alzheimer’s Disease

Fountain of youth—Targeting autophagy in aging

Preservation of an Aging-Associated Mitochondrial Signature in Advanced Human Neuronal Models

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