Abstract
Neurodegenerative dementias are the most common group of neurodegenerative diseases affecting more than 40 million people worldwide. One of these diseases is frontotemporal dementia (FTD), an early onset dementia and one of the leading causes of dementia in people under the age of 60. FTD is a heterogeneous group of neurodegenerative disorders with pathological accumulation of particular proteins in neurons and glial cells including the microtubule-associated protein tau, which is deposited in its hyperphosphorylated form in about half of all patients with FTD. As for other patients with dementia, there is currently no cure for patients with FTD and thus several lines of research focus on the characterization of underlying pathogenic mechanisms with the goal to identify therapeutic targets. In this review, we provide an overview of reported disease phenotypes in induced pluripotent stem cell (iPSC)-derived neurons and glial cells from patients with tau-associated FTD with the aim to highlight recent progress in this fast-moving field of iPSC disease modeling. We put a particular focus on genetic forms of the disease that are linked to mutations in the gene encoding tau and summarize mutation-associated changes in FTD patient cells related to tau splicing and tau phosphorylation, microtubule function and cell metabolism as well as calcium homeostasis and cellular stress. In addition, we discuss challenges and limitations but also opportunities using differentiated patient-derived iPSCs for disease modeling and biomedical research on neurodegenerative diseases including FTD.
Highlights
Human induced pluripotent stem cells have been widely used for research on neurological disorders including neurodegenerative diseases. iPSCs are generated from differentiated somatic cells, usually fibroblasts or peripheral blood mononuclear cells, by overexpression of the reprogramming factors Oct4, Klf4, Sox2 and c-Myc (Takahashi and Yamanaka, 2006; Takahashi et al, 2007; Figure 1)
Identification of 61 overlapping genes linked to calcium-dependent presynaptic function and GABAergic signaling; genes significantly enriched for frontotemporal dementia (FTD) risk variants; some overlap of gene expression signatures in MAPT R406W iPSC-derived neurons with postmortem brain tissue of progressive supranuclear palsy (PSP) patients Formation of βIII-tubulin+ puncta and impaired mitochondrial transport with rescue by the microtubule-stabilizing compound Epothilone D
Most of the studies were performed on cortical neurons as the main affected cell type in frontotemporal lobar degeneration (FTLD)-tau while few studies focused on other neural subtypes such as dopaminergic neurons, astrocytes or oligodendrocytes, which are heavily involved by the disease
Summary
Human induced pluripotent stem cells (iPSCs) have been widely used for research on neurological disorders including neurodegenerative diseases. iPSCs are generated from differentiated somatic cells, usually fibroblasts or peripheral blood mononuclear cells, by overexpression of the reprogramming factors Oct4, Klf4, Sox2 and c-Myc (Takahashi and Yamanaka, 2006; Takahashi et al, 2007; Figure 1). Identification of 61 overlapping genes linked to calcium-dependent presynaptic function and GABAergic signaling; genes significantly enriched for FTD risk variants; some overlap of gene expression signatures in MAPT R406W iPSC-derived neurons with postmortem brain tissue of PSP patients Formation of βIII-tubulin+ puncta and impaired mitochondrial transport with rescue by the microtubule-stabilizing compound Epothilone D
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