Generation of two iPSC lines with either a heterozygous V717I or a heterozygous KM670/671NL mutation in the APP gene

Frederiksen, Henriette R.; Holst, Bjørn; Ramakrishna, Sarayu; Muddashetty, Ravi; Schmid, Benjamin; Freude, Kristine

doi:10.1016/j.scr.2018.101368

Cited by 14 publications

(9 citation statements)

References 3 publications

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“…Neurons were differentiated from hiPSCs derived from two patients carrying fAD-linked PSEN1 mutations and their respective isogenic controls corrected via CRISPR/Cas9 gene editing: L150P and L150P GC (gene corrected) ( Poon et al, 2016 ; Tubsuwan et al, 2016 ), A79V and A79V GC ( Li et al, 2016 ; Pires et al, 2016 ), as well as a healthy control- (K3P53) ( Rasmussen et al, 2014 ) and a CRISPR/Cas9 knock-in hiPSC line carrying the Swedish APP mutation (BioSweden) ( Frederiksen et al, 2019 ). fAD- and control-hiPSCs were successfully differentiated into cortical, glutamatergic forebrain neurons ( Shi et al, 2012 ) ( Figure 1A ).…”

Section: Resultsmentioning

confidence: 99%

“…The hiPSC fAD cell lines were derived from a patient carrying the fAD-linked A79V PSEN1 mutation ( Li et al, 2016 ) and its gene corrected isogenic control A79V GC ( Pires et al, 2016 ), a patient carrying the fAD-linked L150P PSEN1 mutation ( Tubsuwan et al, 2016 ) and its gene corrected isogenic control L150P GC ( Poon et al, 2016 ), a healthy control [K3P53, ( Rasmussen et al, 2014 )] and a CRISPR/Cas9 gene edited knock-in APP Swedish fAD line [BioSweden, ( Frederiksen et al, 2019 )]. All fAD lines have previously been published ( Supplementary Table S1A ).…”

Section: Methodsmentioning

confidence: 99%

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Golgi fragmentation – One of the earliest organelle phenotypes in Alzheimer’s disease neurons

Haukedal

Corsi²,

Gadekar³

et al. 2023

Front. Neurosci.

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Alzheimer’s disease (AD) is the most common cause of dementia, with no current cure. Consequently, alternative approaches focusing on early pathological events in specific neuronal populations, besides targeting the well-studied amyloid beta (Aβ) accumulations and Tau tangles, are needed. In this study, we have investigated disease phenotypes specific to glutamatergic forebrain neurons and mapped the timeline of their occurrence, by implementing familial and sporadic human induced pluripotent stem cell models as well as the 5xFAD mouse model. We recapitulated characteristic late AD phenotypes, such as increased Aβ secretion and Tau hyperphosphorylation, as well as previously well documented mitochondrial and synaptic deficits. Intriguingly, we identified Golgi fragmentation as one of the earliest AD phenotypes, indicating potential impairments in protein processing and post-translational modifications. Computational analysis of RNA sequencing data revealed differentially expressed genes involved in glycosylation and glycan patterns, whilst total glycan profiling revealed minor glycosylation differences. This indicates general robustness of glycosylation besides the observed fragmented morphology. Importantly, we identified that genetic variants in Sortilin-related receptor 1 (SORL1) associated with AD could aggravate the Golgi fragmentation and subsequent glycosylation changes. In summary, we identified Golgi fragmentation as one of the earliest disease phenotypes in AD neurons in various in vivo and in vitro complementary disease models, which can be exacerbated via additional risk variants in SORL1.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Golgi fragmentation – One of the earliest organelle phenotypes in Alzheimer’s disease neurons

Haukedal

Corsi²,

Gadekar³

et al. 2023

Front. Neurosci.

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“…Neurons were differentiated from hiPSCs derived from two patients carrying fAD-linked PSEN1 mutations and their respective isogenic controls corrected via CRISPR/Cas9 gene editing: L150P and L150P GC (gene corrected) (17,18), A79V and A79V GC (19,20), as well as a healthy control-(K3P53) (21) and a CRISPR/Cas9 knock-in hiPSC line carrying the Swedish APP mutation (BioSweden) (22). fAD- and control-hiPSCs were successfully differentiated into cortical, glutamatergic forebrain neurons (23) (Figure 1A) .…”

Section: Resultsmentioning

confidence: 99%

“…The fAD hiPSC cell lines used in the study (Supplementary, Table S1A) have previously been published (17)(18)(19)(20)(21)(22). Generated hiPSC sAD lines (not published) have been characterized and assessed for pluripotency markers and genomic integrity (Supplementary, Figure S2).…”

Section: Hipsc Generation Cell Culture and Neural Differentiationmentioning

confidence: 99%

Golgi fragmentation - One of the earliest organelle phenotypes in Alzheimer’s disease neurons

Haukedal

Corsi

Gadekar

et al. 2022

Preprint

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Alzheimer's disease (AD) is the most common cause of dementia, with no current cure. Consequently, alternative approaches focusing on early pathological events in specific neuronal populations, besides targeting the well-studied Amyloid beta (Ab) accumulations and Tau tangles, are needed. In this study, we have investigated disease phenotypes specific to glutamatergic forebrain neurons and mapped the timeline of their occurrence, by implementing familial and sporadic human induced pluripotent stem cell models as well as the 5xFAD mouse model. We recapitulated characteristic late AD disease phenotypes, such as increased Ab secretion and Tau hyperphosphorylation, as well as previously well documented mitochondrial and synaptic deficits. Intriguingly, we identified Golgi fragmentation as one of the earliest AD phenotypes, indicating potential impairments in protein processing and post-translational modifications. Computational analysis of RNA sequencing data revealed differentially expressed genes involved in glycosylation and glycan patterns, whilst total glycan profiling revealed minor glycosylation differences. This indicates general robustness of glycosylation besides the observed fragmented morphology. Importantly, we identified that genetic variants in Sortilin-related receptor 1 (SORL1) associated with AD could aggravate the Golgi fragmentation and subsequent glycosylation changes. In summary, we identified Golgi fragmentation as one of the earliest disease phenotypes in AD neurons in various in vivo and in vitro complementary disease models, which can be exacerbated via additional risk variants in SORL1.

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“…Generation of two iPS cell lines from the skin biopsy obtained from a healthy male individual of African descent and SNCA @ , GBA @ , GABRB3 @ , BCL7CI/STX1B @ (Tsuang et al 2013;Dickson et al 2018;Tulloch et al 2018) creation of either a heterozygous V717I (London) or a heterozygous KM670/671NL (Swedish) mutation in the APP gene by CRISPR-mediated gene knock-in have been successfully achieved (Frederiksen et al 2018). Recent trend indicates that ethnicity may play a role in AD pathogenesis.…”

Section: Alzheimer's Disease (Ad)mentioning

confidence: 99%

Next Generation Precision Medicine: CRISPR-mediated Genome Editing for the Treatment of Neurodegenerative Disorders

Raikwar

Kikkeri

Sakuru

et al. 2019

J Neuroimmune Pharmacol

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Despite significant advancements in the field of molecular neurobiology especially neuroinflammation and neurodegeneration, the highly complex molecular mechanisms underlying neurodegenerative diseases remain elusive. As a result, the development of the next generation neurotherapeutics has experienced a considerable lag phase. Recent advancements in the field of genome editing offer a new template for dissecting the precise molecular pathways underlying the complex neurodegenerative disorders. We believe that the innovative genome and transcriptome editing strategies offer an excellent opportunity to decipher novel therapeutic targets, develop novel neurodegenerative disease models, develop neuroimaging modalities, develop next-generation diagnostics as well as develop patient-specific precision-targeted personalized therapies to effectively treat neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Frontotemporal dementia etc. Here, we review the latest developments in the field of CRISPR-mediated genome editing and provide unbiased futuristic insights regarding its translational potential to improve the treatment outcomes and minimize financial burden. However, despite significant advancements, we would caution the scientific community that since the CRISPR field is still evolving, currently we do not know the full spectrum of CRISPR-mediated side effects. In the wake of the recent news regarding CRISPR-edited human babies being born in China, we urge the scientific community to maintain high scientific and ethical standards and utilize CRISPR for developing in vitro disease in a dish model, in vivo testing in nonhuman primates and lower vertebrates and for the development of neurotherapeutics for the currently incurable neurodegenerative disorders.

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Generation of two iPSC lines with either a heterozygous V717I or a heterozygous KM670/671NL mutation in the APP gene

Cited by 14 publications

References 3 publications

Golgi fragmentation – One of the earliest organelle phenotypes in Alzheimer’s disease neurons

Golgi fragmentation – One of the earliest organelle phenotypes in Alzheimer’s disease neurons

Golgi fragmentation - One of the earliest organelle phenotypes in Alzheimer’s disease neurons

Next Generation Precision Medicine: CRISPR-mediated Genome Editing for the Treatment of Neurodegenerative Disorders

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