Long non-coding RNA NEAT1_1 ameliorates TDP-43 toxicity in in vivo models of TDP-43 proteinopathy.

Pathological changes involving TDP-43 protein ('TDP-43 proteinopathy') are typical for several neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD). FTLD-TDP cases are characterized by increased binding of TDP-43 to an abundant lncRNA, NEAT1, in the cortex. However it is unclear whether enhanced TDP-43-NEAT1 interaction represents a protective mechanism. We show that accumulation of human TDP-43 leads to upregulation of the constitutive NEAT1 isoform, NEAT1_1, in cultured cells and in the brains of transgenic mice. Further, we demonstrate that overexpression of NEAT1_1 ameliorates TDP-43 toxicity in Drosophila and yeast models of TDP-43 proteinopathy. Thus, NEAT1_1 upregulation may be protective in TDP-43 proteinopathies affecting the brain. Approaches to boost NEAT1_1 expression in the CNS may prove useful in the treatment of these conditions.

The Frontotemporal Dementia Prevention Initiative: Linking Together Genetic Frontotemporal Dementia Cohort Studies.

Around one-third of frontotemporal dementia (FTD) is autosomal dominant with the major genetic causes being mutations in MAPT, GRN and C9orf72. Studying familial forms of FTD can provide a window into the earliest stages of the illness, many years before symptoms start. Large cohort studies have been set up in recent years to better understand this presymptomatic phase, including the Genetic FTD Initiative (GENFI) and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (ARTFL/LEFFTDS) studies. Whilst these studies have focused on the investigation of a variety of aspects of genetic FTD, from understanding the molecular pathogenesis to developing biomarkers, they also have a common goal: finding a way to prevent FTD. Researchers from these cohort studies have therefore come together to form the FTD Prevention Initiative (FPI), which has the overarching aim of promoting clinical trials of new therapies to prevent FTD through creating an international database of participants eligible for trials and uniform standards for conducting such trials. This chapter outlines the work of the FPI so far and its future goals over the next few years.

Risk factors for frontotemporal dementia. / Risikofaktorer for frontotemporal demens.

BAKGRUNN: Risikofaktorer for frontotemporal demens er lite kartlagt. Formålet med denne artikkelen var å gi en oppdatert oversikt over modifiserbare risikofaktorer for frontotemporal demens og vurdere kunnskapsgrunnlaget for kliniske anbefalinger for å redusere risiko for sykdommen. KUNNSKAPSGRUNNLAG: Det ble utført søk i basene PsychInfo, Embase, PubMed og Cochrane i perioden mai 2016-april 2017. Søket ga totalt 137 artikler. 101 artikler ble ekskludert fordi de kun omhandlet genetiske aspekter ved frontotemporal demens og ikke modifiserbare risikofaktorer. Etter å ha lest 36 artikler i fulltekst inkluderte vi 12 artikler som enten var oversiktsartikler eller originalstudier. RESULTATER: Enkelte studier viste sammenheng mellom modifiserbare risikofaktorer og utvikling av frontotemporal demens. I én studie fant man at diabetes ga økt risiko. Tre studier viste at hodetraume kan gi økt risiko for frontotemporal demens og at forekomsten av traumatisk hodeskade var signifikant høyere hos pasienter med frontotemporal demens enn andre former for demens. Autoimmun sykdom kan være forbundet med økt risiko for primær progressiv afasi, en undergruppe av frontotemporal demens. FORTOLKNING: Litteraturen indikerte sammenheng mellom diabetes, hodetraume, autoimmun sykdom og frontotemporal demens. Det finnes per i dag ikke tilstrekkelig kunnskap for å fremme anbefalinger om livsstilsendringer for å forebygge frontotemporal demens på befolkningsnivå.

Progress and Challenges in Frontotemporal Dementia Research: A 20-Year Review.

The landscape of frontotemporal dementia (FTD) has evolved remarkably in recent years and is barely recognizable from two decades ago. Knowledge of the clinical phenomenology, cognition, neuroimaging, genetics, pathology of the different subtypes of FTD, and their relations to other neurodegenerative conditions, has increased rapidly, due in part, to the growing interests into these neurodegenerative brain conditions. This article reviews the major advances in the field of FTD over the past 20 years, focusing primarily on the work of Frontier, the frontotemporal dementia clinical research group, based in Sydney, Australia. Topics covered include clinical presentations (cognition, behavior, neuroimaging), pathology, genetics, and disease progression, as well as interventions and carer directed research. This review demonstrates the improvement in diagnostic accuracy and capacity to provide advice on genetic risks, prognosis, and outcome. The next major challenge will be to capitalize on these research findings to develop effective disease modifying drugs, which are currently lacking.

Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia.

Increased p25, a proteolytic fragment of the regulatory subunit p35, is known to induce aberrant activity of cyclin-dependent kinase 5 (Cdk5), which is associated with neurodegenerative disorders, including Alzheimer's disease. Previously, we showed that replacing endogenous p35 with the noncleavable mutant p35 (Δp35) attenuated amyloidosis and improved cognitive function in a familial Alzheimer's disease mouse model. Here, to address the role of p25/Cdk5 in tauopathy, we generated double-transgenic mice by crossing mice overexpressing mutant human tau (P301S) with Δp35KI mice. We observed significant reduction of phosphorylated tau and its seeding activity in the brain of double transgenic mice compared with the P301S mice. Furthermore, synaptic loss and impaired LTP at hippocampal CA3 region of P301S mice were attenuated by blocking p25 generation. To further validate the role of p25/Cdk5 in tauopathy, we used frontotemporal dementia patient-derived induced pluripotent stem cells (iPSCs) carrying the Tau P301L mutation and generated P301L:Δp35KI isogenic iPSC lines using CRISPR/Cas9 genome editing. We created cerebral organoids from the isogenic iPSCs and found that blockade of p25 generation reduced levels of phosphorylated tau and increased expression of synaptophysin. Together, these data demonstrate a crucial role for p25/Cdk5 in mediating tau-associated pathology and suggest that inhibition of this kinase can remedy neurodegenerative processes in the presence of pathogenic tau mutation.SIGNIFICANCE STATEMENT Accumulation of p25 results in aberrant Cdk5 activation and induction of numerous pathological phenotypes, such as neuroinflammation, synaptic loss, Aß accumulation, and tau hyperphosphorylation. However, it was not clear whether p25/Cdk5 activity is necessary for the progression of these pathological changes. We recently developed the Δp35KI transgenic mouse that is deficient in p25 generation and Cdk5 hyperactivation. In this study, we used this mouse model to elucidate the role of p25/Cdk5 in FTD mutant tau-mediated pathology. We also used a frontotemporal dementia patient-derived induced pluripotent stem cell carrying the Tau P301L mutation and generated isogenic lines in which p35 is replaced with noncleavable mutant Δp35. Our data suggest that p25/Cdk5 plays an important role in tauopathy in both mouse and human model systems.

Demencia frontotemporal variante conductual: biomarcadores, una aproximación a la enfermedad / Biomarkers: A new approach to behavioural variant frontotemporal dementia

Introducción: Las degeneraciones lobares frontotemporales (DLFT) son un grupo de patologías moleculares que se definen en función de la proteína acumulada en el sistema nervioso central. La demencia frontotemporal variante conductual (DFT vc) es el síndrome clínico de presentación más frecuente. Los avances realizados en los últimos anos han contribuido a un mayor conocimiento de esta entidad, que puede ser el modo de presentación de diferentes enfermedades neurodegenerativas. Desarrollo: Se revisa la correlación entre clínica, patología y genética de las DLFT, en especial de la DFT vc, así como los principales biomarcadores de la enfermedad. La anatomía patológica de la DFT vc es muy variada, sin mostrar asociación significativa con ningún subtipo histopatológico concreto. Entre los biomarcadores disponibles, destacan la neuroimagen anatómica y funcional, los biomarcadores analíticos y la genética. Se están disenando fármacos dirigidos contra dianas moleculares concretas implicadas en la patogenia de las DLFT. Conclusiones: La DFT vc es una causa frecuente de demencia. De entre todas las variantes clínicas de las DLFT, es en la que resulta más difícil establecer una relación clínico-patológica. El uso de biomarcadores puede ayudar a predecir la anatomía patológica subyacente, lo que junto al desarrollo de fármacos ligando-específicos ofrece nuevas posibilidades terapéuticas

Introduction: Lobar frontotemporal degeneration (FTLD) encompasses a group of molecular disease defined by the deposition of an abnormal protein in the central nervous system. Behavioural variant frontotemporal dementia (bvFTD) is the most frequent clinical presentation of FTLD. The past two decades of research have contributed to a better understanding of this entity, which may be the first manifestation in many different neurodegenerative disorders. Development: We reviewed correlations between clinical, pathological, and genetic findings and the main disease biomarkers of FTLD, with particular interest in bvFTD. Anatomical pathology findings in FTLD are heterogeneous and the syndrome is not associated with any one specific histopathological type. Promising available biomarkers include structural and functional neuroimaging techniques and biochemical and genetic biomarkers. Disease-modifying drugs designed for specific molecular targets that are implicated in FTLD pathogenesis are being developed. Conclusions: BvFTD is a frequent cause of dementia. Of all the clinical variants of FTLD, behavioural variant is the one in which establishing a correlation between clinical and pathological signs is the most problematic. A biomarker evaluation may help predict the underlying pathology; this approach, in conjunction with the development of disease-modifying drugs, offers new therapeutic possibilities

Fenocopias de la variante conductual de la demencia frontotemporal / Phenocopies of behavioural variant frontotemporal dementia

Introducción: En los últimos años se han detectado casos clínicamente indistinguibles de la variante conductual de la demencia frontotemporal (vcDFT) que presentan buen pronóstico y que se han denominado fenocopias de la vcDFT. Se desconocen los sustratos etiológicos e histopatológicos de estos casos. Material y métodos: Se ha realizado una revisión de la bibliografía existente en PubMed desde 1973 hasta 2012. Resultados: Se han hallado 63 artículos relevantes para la presente revisión. La normalidad de las pruebas de neuroimagen, junto a la preservación de la capacidad funcional, la función ejecutiva y la teoría de la mente son las características que mejor discriminan los casos de vcDFT de las fenocopias. Se desconoce la etiología de las fenocopias de la vcDFT y existen discrepancias sobre si existe neurodegeneración subyacente. Algunos autores sugieren que existiría un trastorno neuropsiquiátrico subyacente, y también se ha identificado una mutación causante de demencia frontotemporal (DFT) en pacientes con vcDFT lentamente progresiva. Los actuales criterios diagnósticos de la vcDFT no permiten diferenciar los casos de fenocopias. Conclusión: Es importante diferenciar la vcDFT progresiva de los casos de fenocopia para ofrecer un pronóstico ajustado a estos pacientes y sus familiares(AU)

Introduction: Cases clinically indistinguishable from behavioural variant frontotemporal dementia (bvFTD) have been described in recent years. Their prognosis is good and they have been labelled as bvFTD phenocopies. Their aetiology and histopathology remain unknown. Material and methods: A review of the literature on PubMed from 1973 to 2012 was undertaken, 63 articles found being relevant. Results: Normal results in neuroimage, functional ability, executive function and theory of mind tests seem to discriminate between bvFTD and phenocopies. The aetiology of bvFTD phenocopy cases is currently unknown and there is disagreement regarding the presence of underlying neurodegeneration. Some authors suggest that these cases could be caused by an underlying neuropsychiatric disorder, and a mutation causing frontotemporal dementia in patients with slowly progressive bvFTD has been identifyed as well. The current diagnostic criteria for bvFTD do not distinguish phenocopy cases. Conclusion: It is important to differentiate progressive bvFTD from phenocopy cases to provide an accurate prognosis to these patients and their families(AU)

Behavioral improvement after chronic administration of coenzyme Q10 in P301S transgenic mice.

Coenzyme Q10 is a key component of the electron transport chain which plays an essential role in ATP production and also has antioxidant effects. Neuroprotective effects of coenzyme Q10 have been reported in both in vitro and in vivo models of neurodegenerative diseases. However, its effects have not been studied in cells or in animals with tau induced pathology. In this report, we administered coenzyme Q10 to transgenic mice with the P301S tau mutation, which causes fronto-temporal dementia in man. These mice develop tau hyperphosphorylation and neurofibrillary tangles in the brain. Coenzyme Q10 improved survival and behavioral deficits in the P301S mice. There was a modest reduction in phosphorylated tau in the cortex of P301S mice. We also examined the effects of coenzyme Q10 treatment on the electron transport chain enzymes, the mitochondrial antioxidant enzymes, and the tricarboxylic acid cycle. There was a significant increase in complex I activity and protein levels, and a reduction in lipid peroxidation. Our data show that coenzyme Q10 significantly improved behavioral deficits and survival in transgenic mice with the P301S tau mutation, upregulated key enzymes of the electron transport chain, and reduced oxidative stress.

Hypoxia induces up-regulation of progranulin in neuroblastoma cell lines.

Progranulin (PGRN) is a widely expressed multifunctional protein, involved in regulation of cell growth and cell cycle progression with a possible involvement in neurodegeneration. We looked for PGRN regulation in three different human neuroblastoma cell lines, following exposure to two different stimuli commonly associated to neurodegeneration: hypoxia and oxidative stress. For gene and protein expression analysis we carried out a quantitative RT-PCR and western blotting analysis. We show that PGRN is strongly up-regulated by hypoxia, through the mitogen-actived protein kinase (MAPK)/extracellular signal-regulated kinase (MEK) signaling cascade. PGRN is not up-regulated by H(2)O(2)-induced oxidative stress. These results suggest that PGRN in the brain could exert a protective role against hypoxic stress, one of principal risk factors involved in frontotemporal dementia pathogenesis.