Dataset Information

Modeling of Frontotemporal Dementia Using iPSC Technology.

ABSTRACT: Frontotemporal dementia (FTD) is caused by the progressive degeneration of the frontal and temporal lobes of the brain. Behavioral variant FTD (bvFTD) is the most common clinical subtype of FTD and pathological subtypes of bvFTD are known as FTD-tau, transactive response (TAR) DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS). Pathological mechanisms of bvFTD are largely unknown. In this study, we investigated the expression of pathological markers, such as p-Tau, TDP-43, and FUS, in the induced pluripotent stem-cell-derived neurons (iPSN) from two sporadic bvFTD patients and one normal subject. We also used an FTD-patient-derived iPSC-line-carrying microtubule-associated protein tau (MAPT) P301L point mutation as positive control for p-Tau expression. Staurosporine (STS) was used to induce cellular stress in order to investigate dynamic cellular responses related to the cell death pathway. As a result, the expression of active caspase-3 was highly increased in the bvFTD-iPSNs compared with control iPSNs in the STS-treated conditions. Other cell-death-related proteins, including Bcl-2-associated X protein (Bax)/Bcl-2 and cytochrome C, were also increased in the bvFTD-iPSNs. Moreover, we observed abnormal expression patterns of TDP-43 and FUS in the bvFTD-iPSNs compared with control iPSNs. We suggest that the iPSC technology might serve as a potential tool to demonstrate neurodegenerative phenotypes of bvFTD, which will be useful for studying pathological mechanisms for FTD as well as related drug screening in the future.

SUBMITTER: Kim M

PROVIDER: S-EPMC7432206 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Modeling of Frontotemporal Dementia Using iPSC Technology.

Kim Minchul M Kim Hee Jin HJ Koh Wonyoung W Li Ling L Heo Hyohoon H Cho Hanna H Lyoo Chul Hyoung CH Seo Sang Won SW Kim Eun-Joo EJ Nakanishi Mahito M Na Duk L DL Song Jihwan J

International journal of molecular sciences 20200727 15

Frontotemporal dementia (FTD) is caused by the progressive degeneration of the frontal and temporal lobes of the brain. Behavioral variant FTD (bvFTD) is the most common clinical subtype of FTD and pathological subtypes of bvFTD are known as FTD-tau, transactive response (TAR) DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS). Pathological mechanisms of bvFTD are largely unknown. In this study, we investigated the expression of pathological markers, such as p-Tau, TDP-43, and FUS, in t ...[more]

PMID: 32727073

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Project description:BACKGROUND:Diagnosing frontotemporal dementia may be challenging. New methods for analysis of regional brain atrophy patterns on magnetic resonance imaging (MRI) could add to the diagnostic assessment. Therefore, we aimed to develop automated imaging biomarkers for differentiating frontotemporal dementia subtypes from other diagnostic groups, and from one another. METHODS:In this retrospective multicenter cohort study, we included 1213 patients (age 67 ± 9, 48% females) from two memory clinic cohorts: 116 frontotemporal dementia, 341 Alzheimer's disease, 66 Dementia with Lewy bodies, 40 vascular dementia, 104 other dementias, 229 mild cognitive impairment, and 317 subjective cognitive decline. Three MRI atrophy biomarkers were derived from the normalized volumes of automatically segmented cortical regions: 1) the anterior vs. posterior index, 2) the asymmetry index, and 3) the temporal pole left index. We used the following performance metrics: area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. To account for the low prevalence of frontotemporal dementia we pursued a high specificity of 95%. Cross-validation was used in assessing the performance. The generalizability was assessed in an independent cohort (n = 200). RESULTS:The anterior vs. posterior index performed with an AUC of 83% for differentiation of frontotemporal dementia from all other diagnostic groups (Sensitivity = 59%, Specificity = 95%, positive likelihood ratio = 11.8, negative likelihood ratio = 0.4). The asymmetry index showed highest performance for separation of primary progressive aphasia and behavioral variant frontotemporal dementia (AUC = 85%, Sensitivity = 79%, Specificity = 92%, positive likelihood ratio = 9.9, negative likelihood ratio = 0.2), whereas the temporal pole left index was specific for detection of semantic variant primary progressive aphasia (AUC = 85%, Sensitivity = 82%, Specificity = 80%, positive likelihood ratio = 4.1, negative likelihood ratio = 0.2). The validation cohort provided corresponding results for the anterior vs. posterior index and temporal pole left index. CONCLUSION:This study presents three quantitative MRI biomarkers, which could provide additional information to the diagnostic assessment and assist clinicians in diagnosing frontotemporal dementia.

Project description:Frontotemporal dementia (FTD) encompasses a spectrum of neurodegenerative diseases with heterogeneous clinical presentations and two predominant types of underlying neuropathology. FTD typically comprises three distinct clinical syndromes: behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), and nonfluent variant primary progressive aphasia (nfvPPA). FTD also frequently overlaps both clinically and neuropathologically with three other neurodegenerative syndromes: corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS). Each syndrome can be associated with one or more underlying neuropathological diagnoses and are referred to as frontotemporal lobar degeneration (FTLD). Although the various FTD syndromes can substantially differ in terms of clinical symptoms and underlying pathology, the symptoms can be broadly categorized into behavioral, cognitive and motor domains. Currently there are no Food and Drug Administration (FDA) approved therapies for the above syndromes except riluzole for ALS. FTD treatment strategies generally rely on off-label use of medications for symptomatic management, and most therapies lack quality evidence from randomized, placebo-controlled clinical trials. For behavioral symptoms, selective serotonin reuptake inhibitors may be effective, while case reports hint at possible efficacy with antipsychotics or anti-epileptics, but use of these latter agents is limited due to concerns regarding side effects. There are no effective therapies for cognitive complaints in FTD, which frequently involve executive function, memory, and language. Motor difficulties associated with FTD may present with parkinsonian symptoms or motor neuron disease, for which riluzole is indicated as therapy. Compared to idiopathic Parkinson's disease, FTD-related atypical parkinsonism is generally not responsive to dopamine replacement therapies, but a small percentage of patients may experience improvement with a trial of carbidopa-levodopa. Physical and occupational therapy remain an important corner stone of motor symptom management in FTD. Speech therapy may also help patients manage symptoms associated with aphasia, apraxia, and dysarthria. Recent advances in the understanding of FTLD pathophysiology and genetics have led to development of potentially disease-modifying therapies as well as symptomatic therapies aimed at ameliorating social and behavioral deficits.

Project description:Frontotemporal dementia (FTD) is amongst the most prevalent early onset dementias and even though it is clinically, pathologically and genetically heterogeneous, a crucial involvement of metabolic perturbations in FTD pathology is being recognized. However, changes in metabolism at the cellular level, implicated in FTD and in neurodegeneration in general, are still poorly understood. Here we generate induced human pluripotent stem cells (hiPSCs) from patients carrying mutations in CHMP2B (FTD3) and isogenic controls generated via CRISPR/Cas9 gene editing with subsequent neuronal and glial differentiation and characterization. FTD3 neurons show a dysregulation of glutamate-glutamine related metabolic pathways mapped by 13C-labelling coupled to mass spectrometry. FTD3 astrocytes show increased uptake of glutamate whilst glutamate metabolism is largely maintained. Using quantitative proteomics and live-cell metabolic analyses, we elucidate molecular determinants and functional alterations of neuronal and glial energy metabolism in FTD3. Importantly, correction of the mutations rescues such pathological phenotypes. Notably, these findings implicate dysregulation of key enzymes crucial for glutamate-glutamine homeostasis in FTD3 pathogenesis which may underlie vulnerability to neurodegeneration. Neurons derived from human induced pluripotent stem cells (hiPSCs) of patients carrying mutations in CHMP2B (FTD3) display major metabolic alterations compared to CRISPR/Cas9 generated isogenic controls. Using quantitative proteomics, 13C-labelling coupled to mass spectrometry metabolic mapping and seahorse analyses, molecular determinants and functional alterations of neuronal and astrocytic energy metabolism in FTD3 were characterized. Our findings implicate dysregulation of glutamate-glutamine homeostasis in FTD3 pathogenesis. In addition, FTD3 neurons recapitulate glucose hypometabolism observed in FTD patient brains. The impaired mitochondria function found here is concordant with disturbed TCA cycle activity and decreased glycolysis in FTD3 neurons. FTD3 neuronal glutamine hypermetabolism is associated with up-regulation of PAG expression and, possibly, ROS production. Distinct compartments of glutamate metabolism can be suggested for the FTD3 neurons. Endogenous glutamate generated from glutamine via PAG may enter the TCA cycle via AAT (left side of neuron) while exogenous glutamate taken up from the extracellular space may be incorporated into the TCA cycle via GDH (right side of the neuron) FTD3 astrocytic glutamate uptake is upregulated whilst glutamate metabolism is largely maintained. Finally, pharmacological reversal of glutamate hypometabolism manifesting from decreased GDH expression should be explored as a novel therapeutic intervention for treating FTD3.

Dataset Information

Modeling of Frontotemporal Dementia Using iPSC Technology.

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Modeling of Frontotemporal Dementia Using iPSC Technology.

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