Neurons Derived from Induced Pluripotent Stem Cells of Patients with Down Syndrome Reproduce Early Stages of Alzheimer’s Disease Type Pathology in vitro

Дашинимаев, Э. Б.; Artyuhov, Alexander; Bolshakov, A D; Vorotelyak, E. A.; Vasiliev, A. V.

doi:10.3233/jad-160945

Cited by 28 publications

(15 citation statements)

References 37 publications

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“…DS patients develop early onset AD, thought to result from triplication of the APP gene as part of trisomy 21 [97]. DS iPSC-derived neurons show elevations in Aβ secretion and phosphorylated tau similar to that caused by FAD-linked mutations [98][99][100][101]. Intriguingly, deletion of the supernumerary copy of APP from DS cells was able to restore Aβ production to control levels and correct many of the gene expression alterations caused by trisomy 21, but was not able to restore altered tau phosphorylation, indicating Aβ-dependent and independent phenotypes in DS [101].…”

Section: Human Neural Progenitor Cell and Neuron Modelsmentioning

confidence: 99%

Modeling Alzheimer’s disease with iPSC-derived brain cells

2019

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Alzheimer's disease is a devastating neurodegenerative disorder with no cure. Countless promising therapeutics have shown efficacy in rodent Alzheimer's disease models yet failed to benefit human patients. While hope remains that earlier intervention with existing therapeutics will improve outcomes, it is becoming increasingly clear that new approaches to understand and combat the pathophysiology of Alzheimer's disease are needed. Human induced pluripotent stem cell (iPSC) technologies have changed the face of preclinical research and iPSC-derived cell types are being utilized to study an array of human conditions, including neurodegenerative disease. All major brain cell types can now be differentiated from iPSCs, while increasingly complex co-culture systems are being developed to facilitate neuroscience research. Many cellular functions perturbed in Alzheimer's disease can be recapitulated using iPSC-derived cells in vitro, and co-culture platforms are beginning to yield insights into the complex interactions that occur between brain cell types during neurodegeneration. Further, iPSC-based systems and genome editing tools will be critical in understanding the roles of the numerous new genes and mutations found to modify Alzheimer's disease risk in the past decade. While still in their relative infancy, these developing iPSC-based technologies hold considerable promise to push forward efforts to combat Alzheimer's disease and other neurodegenerative disorders.

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Section: Human Neural Progenitor Cell and Neuron Modelsmentioning

confidence: 99%

Modeling Alzheimer’s disease with iPSC-derived brain cells

2019

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“…Genome editing technology could also be used for mutations’ correction, generating an isogenic control line [18]. Interestingly, iPSCs derived from iPSCs of patients with Down Syndrome, which usually have a high risk of early AD development, allowed the understanding of AD-like initial cellular hallmarks [19]. IPSCs also assume an important role when it comes to drug screening models.…”

Section: Uses Of Ipscs In Neurodegenerative Diseasesmentioning

confidence: 99%

From Neuronal Differentiation of iPSCs to 3D Neuro-Organoids: Modelling and Therapy of Neurodegenerative Diseases

Bordoni

Rey

Fantini

et al. 2018

IJMS

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In the last decade, the advances made into the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) led to great improvements towards their use as models of diseases. In particular, in the field of neurodegenerative diseases, iPSCs technology allowed to culture in vitro all types of patient-specific neural cells, facilitating not only the investigation of diseases’ etiopathology, but also the testing of new drugs and cell therapies, leading to the innovative concept of personalized medicine. Moreover, iPSCs can be differentiated and organized into 3D organoids, providing a tool which mimics the complexity of the brain’s architecture. Furthermore, recent developments in 3D bioprinting allowed the study of physiological cell-to-cell interactions, given by a combination of several biomaterials, scaffolds, and cells. This technology combines bio-plotter and biomaterials in which several types of cells, such as iPSCs or differentiated neurons, can be encapsulated in order to develop an innovative cellular model. IPSCs and 3D cell cultures technologies represent the first step towards the obtainment of a more reliable model, such as organoids, to facilitate neurodegenerative diseases’ investigation. The combination of iPSCs, 3D organoids and bioprinting will also allow the development of new therapeutic approaches. Indeed, on the one hand they will lead to the development of safer and patient-specific drugs testing but, also, they could be developed as cell-therapy for curing neurodegenerative diseases with a regenerative medicine approach.

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“…Finally, the computational analysis identified several genes that represent the target of most of the significant miRNAs (see Table ). Of interest, some of these genes have been reported implicated in diseases with cognitive impairment, for example, BRI3, RGS6, DIP2A, ZBTB16, BACE2, SIRBP1, IGF2BP2, FCRL5, RTN3, FAM46A, MCF2L, SPI1, and TREM1 in Alzheimer's disease (Abd‐Elrahman, Hamilton, Vasefi, & Ferguson, ; Chung et al, ; Comabella et al, ; Dashinimaev, Artyuhov, Bolshakov, Vorotelyak, & Vasiliev, ; De Jager et al, ; Gaikwad et al, ; Gasparoni et al, ; Matsuda, Matsuda, & D'Adamio, ; Moon et al, ; Replogle et al, ; Schott et al, ; Shi, Ge, He, Hu, & Yan, ); or in clinical conditions characterized by behavioral changes, such as NTNG2 in cognitive abnormalities associated with defective axonal amygdalar projections (Huang et al, ) or bipolar disorders (Egger et al, ), or RAB11FIP5, WARS, and HES6 in depression and other mood disorders (Bacaj, Ahmad, Jurado, Malenka, & Sudhof, ; Glubb, Joyce, & Kennedy, ; Musante et al, ). Furthermore, the experimental ablation of CACNA1H , a gene already associated with the RR course of MS (Sadovnick et al, ), was able to trigger affective disorders including anxiety and hippocampus‐dependent recognition memories (Gangarossa, Laffray, Bourinet, & Valjent, ).…”

Section: Discussionmentioning

confidence: 99%

Association between miRNAs expression and cognitive performances of Pediatric Multiple Sclerosis patients: A pilot study

et al. 2019

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Introduction The Pediatric onset of Multiple Sclerosis (PedMS) occurs in up to 10% of all cases. Cognitive impairment is one of the frequent symptoms, exerting severe impact in patients’ quality of life and school performances. The underlying pathogenic mechanisms are not fully understood, and molecular markers predictive of cognitive dysfunctions need to be identified. On these grounds, we searched for molecular signature/s (i.e., miRNAs and target genes) associated with cognitive impairment in a selected population of PedMS patients. Additionally, changes of their regional brain volumes associated with the miRNAs of interest were investigated. Methods Nineteen PedMS subjects received a full cognitive evaluation; total RNA from peripheral blood samples was processed by next‐generation sequencing followed by a bioinformatics/biostatistics analysis. Results The expression of 11 miRNAs significantly correlated with the scores obtained at different cognitive tests; among the others, eight miRNAs correlated with the Trail Making Tests. The computational target prediction identified 337 genes targeted by the miRNAs of interest; a tangled network of molecular connections was hypothesized, where genes like BST1, NTNG2, SPTB, and STAB1 , already associated with cognitive dysfunctions, were nodes of the net. Furthermore, the expression of some miRNAs significantly correlated with cerebral volumes, for example, four miRNAs with the cerebellum cortex. Conclusions As far as we know, this is the first evaluation exploring miRNAs in the cognitive performances of PedMS. Although none of these results survived the multiple tests’ corrections, we believe that they may represent a step forward the identification of biomarkers useful for monitoring and targeting the onset/progression of cognitive impairments in MS.

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Neurons Derived from Induced Pluripotent Stem Cells of Patients with Down Syndrome Reproduce Early Stages of Alzheimer’s Disease Type Pathology in vitro

Cited by 28 publications

References 37 publications

Modeling Alzheimer’s disease with iPSC-derived brain cells

Modeling Alzheimer’s disease with iPSC-derived brain cells

From Neuronal Differentiation of iPSCs to 3D Neuro-Organoids: Modelling and Therapy of Neurodegenerative Diseases

Association between miRNAs expression and cognitive performances of Pediatric Multiple Sclerosis patients: A pilot study

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