Familial Alzheimer’s disease-associated PSEN1 mutations affect neurodevelopment through increased Notch signaling

Hurley, Erin M.; Mozolewski, Paweł; Dobrowolski, Radoslaw; Hsieh, Jenny

doi:10.1016/j.stemcr.2023.05.018

Cited by 18 publications

(9 citation statements)

References 48 publications

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“…The observed reduced neuronal excitability in iNs in this study is consistent with previous findings on PSEN1 fAD mutations. For instance, cortical organoids with an L345F mutation displayed reduced extracellular activity measured by multi-electrode array analysis compared to its isogenic control, likely due to altered notch signaling (Hurley et al 2023). The A246E cell line used in this study, was demonstrated to have a deficiency in Notch1 in iNs, resulting in susceptibility to ferroptosis (Greenough et al 2022).…”

Section: Discussionmentioning

confidence: 86%

“…https://www.alzforum.org/mutations/psen-1). In addition to disrupted amyloid precursor protein (APP) processing and plaque formation, PSEN1 mutations induce early changes in neurons, including, increased susceptibility to Aβ (Armijo et al 2017) and ferroptosis (Greenough et al 2022), dysregulated neurogenesis and differentiation (Arber et al 2021;Hurley et al 2023), decreased neurite outgrowth (Dowjat et al 1999;Furukawa et al 1998;Balez et al 2016;Ghatak et al 2019), endosomal dysfunction (Kwart et al 2019) and neuronal excitability (Hurley et al 2023;Vitale et al 2021;Chen et al 2021). These studies highlight the complex role of presenilin-1 (PSEN1) plays in multiple cellular, and the need to understand how specific mutations affect neuronal function.…”

Section: Introductionmentioning

confidence: 99%

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Alzheimer’s disease induced neurons bearingPSEN1mutations exhibit reduced excitability

Maksour,

Finol-Urdaneta,

Hulme

et al. 2024

Preprint

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Alzheimer's disease (AD) is a devastating neurodegenerative condition that affects memory and cognition, characterized by neuronal loss and currently lacking a cure. Mutations in PSEN1 (Presenilin 1) are among the most common causes of early-onset familial AD (fAD). While changes in neuronal excitability are believed to be early indicators of AD progression, the link between PSEN1 mutations and neuronal excitability remains to be fully elucidated. This study examined induced pluripotent stem cell (iPSC)-derived NGN2 induced neurons (iNs) from fAD patients with PSEN1 mutations S290C or A246E, alongside CRISPR-corrected isogenic cell lines, to investigate early changes in excitability. Electrophysiological profiling revealed reduced excitability in both PSEN1 mutant iNs compared to their isogenic controls. Neurons bearing S290C and A246E mutations exhibited divergent passive membrane properties compared to isogenic controls, suggesting distinct effects of PSEN1 mutations on neuronal excitability. Additionally, both PSEN1 backgrounds exhibited higher current density of voltage-gated potassium (Kv) channels relative to their isogenic iNs, while displaying comparable voltage-gated sodium (Nav) channel current density. This suggests that the Nav/Kv imbalance contributes to impaired neuronal firing in fAD iNs. Deciphering these early cellular and molecular changes in AD is crucial for understanding the disease pathogenesis.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Alzheimer’s disease induced neurons bearingPSEN1mutations exhibit reduced excitability

Maksour,

Finol-Urdaneta,

Hulme

et al. 2024

Preprint

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“…This research is interesting since Notch is a γ-secretase substrate. It was also reported that PSEN1 L435F mutation caused a gain of function in human iPSC-derived 3D cortical spheroids and increased Aβ43 levels [78]. This peptide also increased in the symptomatic PSEN1(A431E) mutation carrier.…”

Section: Mirnas Altered In Mscs Derived From the Psen1(a431e) Symptom...mentioning

confidence: 82%

Mesenchymal Stem Cells from Familial Alzheimer’s Patients Express MicroRNA Differently

Rochín-Hernández,

Padilla-Cristerna

et al. 2024

IJMS

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the predominant form of dementia globally. No reliable diagnostic, predictive techniques, or curative interventions are available. MicroRNAs (miRNAs) are vital to controlling gene expression, making them valuable biomarkers for diagnosis and prognosis. This study examines the transcriptome of olfactory ecto-mesenchymal stem cells (MSCs) derived from individuals with the PSEN1(A431E) mutation (Jalisco mutation). The aim is to determine whether this mutation affects the transcriptome and expression profile of miRNAs and their target genes at different stages of asymptomatic, presymptomatic, and symptomatic conditions. Expression microarrays compare the MSCs from mutation carriers with those from healthy donors. The results indicate a distinct variation in the expression of miRNAs and mRNAs among different symptomatologic groups and between individuals with the mutation. Using bioinformatics tools allows us to identify target genes for miRNAs, which in turn affect various biological processes and pathways. These include the cell cycle, senescence, transcription, and pathways involved in regulating the pluripotency of stem cells. These processes are closely linked to inter- and intracellular communication, vital for cellular functioning. These findings can enhance our comprehension and monitoring of the disease’s physiological processes, identify new disorder indicators, and develop innovative treatments and diagnostic tools for preventing or treating AD.

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“…iPSC-based researches have achieved massive inspiring fruition in various diseases like amyotrophic lateral sclerosis[ 42 ], Huntington's disease[ 43 ], blood diseases[ 44 ] and spinal muscular atrophy[ 45 ]. Using patient iPSCs-derived cortical spheroids, the mechanism of PSEN1 L435F mutation affecting neurodevelopment by increasing Notch signalling in familial Alzheimer’s disease was revealed[ 46 ]. Injection of islets derived from human iPSCs effectively restored endogenous insulin secretion and improved glycemic control in non-human primates[ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic correction of induced pluripotent stem cells from a DFNA36 patient results in morphologic and functional recovery of derived hair cell-like cells

Luo,

Wu,

Zhang

et al. 2024

Stem Cell Res Ther

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Background TMC1 is one of the most common deafness genes causing DFNA36. Patient-derived human induced pluripotent stem cells (iPSCs) provide an opportunity to modelling diseases. TMC1 p.M418K mutation in human is orthologous to Beethoven mice. Here, we investigated the differentiation, morphology and electrophysiological properties of hair cell-like cells (HC-like cells) derived from DFNA36 patient. Methods Inner ear HC-like cells were induced from iPSCs derived from DFNA36 (TMC1 p.M418K) patient (M+/−), normal control (M+/+) and genetic corrected iPSCs (M+/C). Immunofluorescence, scanning electron microscopy and whole-cell patch-clamp were used to study the mechanism and influence of TMC1 p.M418K mutation. Results In this study we successfully generated HC-like cells from iPSCs with three different genotypes. HC-like cells from M+/− showed defected morphology of microvilli and physiological properties compared to M+/+. HC-like cells from M+/C showed recovery in morphology of microvilli and physiological properties. Conclusions Our results indicate that TMC1 p.M418K mutation didn’t influence inner ear hair cell differentiation but the morphology of microvilli and electrophysiological properties and gene correction induced recovery. CRISPR/Cas9 gene therapy is feasible in human patient with TMC1 p.M418K mutation.

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Familial Alzheimer’s disease-associated PSEN1 mutations affect neurodevelopment through increased Notch signaling

Cited by 18 publications

References 48 publications

Alzheimer’s disease induced neurons bearingPSEN1mutations exhibit reduced excitability

Alzheimer’s disease induced neurons bearingPSEN1mutations exhibit reduced excitability

Mesenchymal Stem Cells from Familial Alzheimer’s Patients Express MicroRNA Differently

Genetic correction of induced pluripotent stem cells from a DFNA36 patient results in morphologic and functional recovery of derived hair cell-like cells

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