Applying gene‐editing technology to elucidate the functional consequence of genetic and epigenetic variation in Alzheimer’s disease

Schrauben, Michael; Dempster, Emma; Lunnon, Katie

doi:10.1111/bpa.12881

Cited by 9 publications

(6 citation statements)

References 85 publications

(94 reference statements)

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“…Accordingly, individual genetic contributions to AD risk can be deconvoluted within otherwise genetically identical (i.e., isogenic) sets of hiPSC-based cellular and tissue models. In the context of AD, this gene-editing approach has been implemented by generating panels of isogenic hiPSCs harboring familial ( Konttinen et al, 2019 ; Kwart et al, 2019 ; Schrauben et al, 2020 ) and sporadic AD mutations, with examples of the latter detailed in the following section.…”

Section: Introductionmentioning

confidence: 99%

Building in vitro models of the brain to understand the role ofAPOEin Alzheimer’s disease

Pinals

Tsai

2022

Life Sci. Alliance

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Alzheimer’s disease (AD) is a devastating, complex, and incurable disease that represents an increasingly problematic global health issue. The etiology of sporadic AD that accounts for a vast majority of cases remains poorly understood, with no effective therapeutic interventions. Genetic studies have identified AD risk genes including the most prominent, APOE, of which the ɛ4 allele increases risk in a dose-dependent manner. A breakthrough discovery enabled the creation of human induced pluripotent stem cells (hiPSCs) that can be differentiated into various brain cell types, facilitating AD research in genetically human models. Herein, we provide a brief background on AD in the context of APOE susceptibility and feature work employing hiPSC-derived brain cell and tissue models to interrogate the contribution of APOE in driving AD pathology. Such models have delivered crucial insights into cellular mechanisms and cell type–specific roles underlying the perturbed biological functions that trigger pathogenic cascades and propagate neurodegeneration. Collectively, hiPSC-based models are envisioned to be an impactful platform for uncovering fundamental AD understanding, with high translational value toward AD drug discovery and testing.

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Section: Introductionmentioning

confidence: 99%

Building in vitro models of the brain to understand the role ofAPOEin Alzheimer’s disease

Pinals

Tsai

2022

Life Sci. Alliance

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“…The same methods can be used to study alternative splicing in AD by replacing gene transcription levels with intron excision levels, as demonstrated by a recent study that linked AD risk loci to altered intron usage in PTK2B, PICALM and CLU which are known AD risk loci (35). These integrative studies of GWAS summary statistics and transcription data extended the pool of AD candidate genes and refined known associations by providing new insights, which can now guide the development of functional studies, which are described elsewhere in this mini-symposium series (36).…”

Section: Designing a Well-powered Study Of The Aging Brain By Leveragmentioning

confidence: 94%

Considerations for integrative multi‐omic approaches to explore Alzheimer's disease mechanisms

Klein

Jager

2020

Brain Pathology

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The past decade has seen the maturation of multiple different forms of high‐dimensional molecular profiling to the point that these methods could be deployed in initially hundreds and more recently thousands of human samples. In the field of Alzheimer's disease (AD), these profiles have been applied to the target organ: the aging brain. In a growing number of cases, the same samples were profiled with multiple different approaches, yielding genetic, transcriptomic, epigenomic and proteomic data. Here, we review lessons learned so far as we move beyond quantitative trait locus (QTL) analyses which map the effect of genetic variation on molecular features to integrate multiple levels of “omic” data in an effort to identify the molecular drivers of AD. One thing is clear: no single layer of molecular or “omic” data is sufficient to capture the variance of AD or aging‐related cognitive decline. Nonetheless, reproducible findings are emerging from current efforts, and there is evidence of convergence using different approaches. Thus, we are on the cusp of an acceleration of truly integrative studies as the availability of large numbers of well‐characterized brain samples profiled in three or more dimensions enables the testing, comparison and refinement of analytic methods with which to dissect the molecular architecture of the aging brain.

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“…Clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease9 (CRISPR/Cas9) is a new gene editing technology that targets any genomic locus using only a complex nuclease protein with short RNA as a site-specific endonuclease. CRISPR/Cas9 has been used in the field of cancer research to edit genomes to examine the mechanisms of tumorigenesis and development ( Zhang H. et al, 2021 ) and explore the complex interactions and disruptions in genes that contribute to Huntington’s disease (HD, a neurodegenerative disease; Tabrizi et al, 2020 ) and AD ( Schrauben et al, 2020 ). AD and PNDs may have similar mechanisms and gene effects, and CRISPR/Cas9 may be used in future studies of PNDs.…”

Section: Treatmentsmentioning

confidence: 99%

The NLRP3 inflammasome is a potential mechanism and therapeutic target for perioperative neurocognitive disorders

et al. 2023

Front. Aging Neurosci.

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Perioperative neurocognitive disorders (PNDs) are frequent complications associated with cognitive impairment during the perioperative period, including acute postoperative delirium and long-lasting postoperative cognitive dysfunction. There are some risk factors for PNDs, such as age, surgical trauma, anesthetics, and the health of the patient, but the underlying mechanism has not been fully elucidated. Pyroptosis is a form of programmed cell death that is mediated by the gasdermin protein and is involved in cognitive dysfunction disorders. The canonical pathway induced by nucleotide oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasomes contributes to PNDs, which suggests that targeting NLRP3 inflammasomes may be an effective strategy for the treatment of PNDs. Therefore, inhibiting upstream activators and blocking the assembly of the NLRP3 inflammasome may attenuate PNDs. The present review summarizes recent studies and systematically describes the pathogenesis of NLRP3 activation and regulation and potential therapeutics targeting NLRP3 inflammasomes in PNDs patients.

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Applying gene‐editing technology to elucidate the functional consequence of genetic and epigenetic variation in Alzheimer’s disease

Cited by 9 publications

References 85 publications

Building in vitro models of the brain to understand the role ofAPOEin Alzheimer’s disease

Building in vitro models of the brain to understand the role ofAPOEin Alzheimer’s disease

Considerations for integrative multi‐omic approaches to explore Alzheimer's disease mechanisms

The NLRP3 inflammasome is a potential mechanism and therapeutic target for perioperative neurocognitive disorders

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