Mouse models of frontotemporal dementia: A comparison of phenotypes with clinical symptomatology

Ahmed, Rebekah M.; Irish, Muireann; Eersel, Janet van; Ittner, Arne; Ke, Yazi D.; Volkerling, Alexander; Hoven, Julia van der; Tanaka, Kimi; Karl, Tim; Kassiou, Michael; Kril, Jillian J.; Piguet, Olivier; Götz, Jürgen; Kiernan, Matthew C.; Halliday, Glenda M.; Hodges, John R.; Ittner, Lars M.

doi:10.1016/j.neubiorev.2017.01.004

Cited by 27 publications

(18 citation statements)

References 168 publications

(226 reference statements)

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“…Features of motor system dysfunction were notably absent in progranulin models, replicating their absence in FTD caused by GRN mutation. Conversely, models of tau‐associated FTD (not covered within this review) do exhibit motor phenotypes in addition to behavioural and cognitive symptoms although these are not typically found in FTD caused by mutation in MAPT .…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 97%

“…In rodents, these include phenotypes and pathology reminiscent of behavioural variant FTD (Table S1, Figure ). However, relating behavioural changes in rodents to clinical features is challenging and generally implied by assuming that similar networks control the same behaviours in mice and humans . Phenotypes more specific to FTD are generally considered to be the presence of altered sociability and behavioural changes in anxiety and compulsivity.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Review: Modelling the pathology and behaviour of frontotemporal dementia

Solomon

Mitchell

Salcher-Konrad

et al. 2019

Neuropathology Appl Neurobio

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Frontotemporal dementia (FTD) encompasses a collection of clinically and pathologically diverse neurological disorders. Clinical features of behavioural and language dysfunction are associated with neurodegeneration, predominantly of frontal and temporal cortices. Over the past decade, there have been significant advances in the understanding of the genetic aetiology and neuropathology of FTD which have led to the creation of various disease models to investigate the molecular pathways that contribute to disease pathogenesis. The generation of in vivo models of FTD involves either targeting genes with known disease‐causative mutations such as GRN and C9orf72 or genes encoding proteins that form the inclusions that characterize the disease pathologically, such as TDP‐43 and FUS. This review provides a comprehensive summary of the different in vivo model systems used to understand pathomechanisms in FTD, with a focus on disease models which reproduce aspects of the wide‐ranging behavioural phenotypes seen in people with FTD. We discuss the emerging disease pathways that have emerged from these in vivo models and how this has shaped our understanding of disease mechanisms underpinning FTD. We also discuss the challenges of modelling the complex clinical symptoms shown by people with FTD, the confounding overlap with features of motor neuron disease, and the drive to make models more disease‐relevant. In summary, in vivo models can replicate many pathological and behavioural aspects of clinical FTD, but robust and thorough investigations utilizing shared features and variability between disease models will improve the disease‐relevance of findings and thus better inform therapeutic development.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 97%

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Review: Modelling the pathology and behaviour of frontotemporal dementia

Solomon

Mitchell

Salcher-Konrad

et al. 2019

Neuropathology Appl Neurobio

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“…Such work has a crucial preclinical phase via drug discovery and development of therapeutic approaches in vitro and animal models, including pluripotent stem cells derived from patients with defined diseases and transgenic mice that can be used to generate model neuronal systems. [95][96][97] Proposed disease-modification strategies have included antitau antibodies and microtubule stabilization, stimulation of progranulin expression and release, modulation of autoimmunity and neuroinflammation (particularly relevant to GRN mutations) and, most dramatically (informed by recent progress in Huntington's disease), silencing of toxic C9orf72 RNA messengers using antisense oligonucleotides. 83,98 To date, the value and feasibility of these strategies remain unproven in FTD.…”

Section: Future Prospectsmentioning

confidence: 99%

Frontotemporal Dementia: A Clinical Review

et al. 2019

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Frontotemporal dementias are a clinically, neuroanatomically, and pathologically diverse group of diseases that collectively constitute an important cause of young-onset dementia. Clinically, frontotemporal dementias characteristically strike capacities that define us as individuals, presenting broadly as disorders of social behavior or language. Neurobiologically, these diseases can be regarded as “molecular nexopathies,” a paradigm for selective targeting and destruction of brain networks by pathogenic proteins. Mutations in three major genes collectively account for a substantial proportion of behavioral presentations, with far-reaching implications for the lives of families but also potential opportunities for presymptomatic diagnosis and intervention. Predicting molecular pathology from clinical and radiological phenotypes remains challenging; however, certain patterns have been identified, and genetically mediated forms of frontotemporal dementia have spearheaded this enterprise. Here we present a clinical roadmap for diagnosis and assessment of the frontotemporal dementias, motivated by our emerging understanding of the mechanisms by which pathogenic protein effects at the cellular level translate to abnormal neural network physiology and ultimately, complex clinical symptoms. We conclude by outlining principles of management and prospects for disease modification.

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“…Phosphorylation of tau leads to changes in conformation, solubility and activity under both physiological and pathological conditions 13 . Pathogenic mutations in the tau-encoding MAPT gene underlying familial frontotemporal dementia (FTD) have assisted in the generation of multiple transgenic mouse models that recapitulate pathological and/or behavioural aspects of dementia 14 – 16 . This includes the TAU58/2 line more recently developed by us; TAU58/2 mice express human P301S mutant tau in neurons and present with progressive tau hyperphosphorylation and NFT pathology, as well as early-onset motor, behavioural and learning deficits 17 .…”

Section: Introductionmentioning

confidence: 99%

“…of dementia [14][15][16] . This includes the TAU58/2 line more recently developed by us; TAU58/2 mice express human P301S mutant tau in neurons and present with progressive tau hyperphosphorylation and NFT pathology, as well as early-onset motor, behavioural and learning deficits 17 .…”

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confidence: 99%

Contribution of endogenous antibodies to learning deficits and astrocytosis in human P301S mutant tau transgenic mice

Hoven

Hummel

Przybyla

et al. 2020

Sci Rep

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Antibodies have been explored extensively as a potential therapeutic for Alzheimer's disease, where amyloid-β (Aβ) peptides and the tau protein deposit in patient brains. While the major focus of antibody-based therapy development was on Aβ, arguably with limited success in clinical trials, targeting tau has become an emerging strategy, possibly extending therapies to dementias with isolated tau pathology. Interestingly, low titres of autoantibodies to pathological tau have been described in humans and transgenic mouse models, but their pathophysiological relevance remained elusive. Here, we used two independent approaches to deplete the B-cell lineage and hence antibody formation in human P301S mutant tau transgenic mice, TAU58/2. TAU58/2 mice were either crossed with the B-cell-deficient Ighm knockout line (muMT −/−) or treated with anti-CD20 antibodies that target B-cell precursors. In both models, B-cell depletion significantly reduced astrocytosis in TAU58/2 mice. Only when B-cells were absent throughout life, in TAU58/2.muMT −/− mice, were spatial learning deficits moderately aggravated while motor performance improved as compared to B-cell-competent TAU58/2 mice. This was associated with changes in brain region-specific tau solubility. No other relevant behavioural or neuropathological changes were observed in TAU58/2 mice in the absence of B-cells/antibodies. Taken together, our data suggests that the presence of antibodies throughout life contributes to astrocytosis in TAU58/2 mice and limits learning deficits, while other deficits and neuropathological changes appear to be independent of the presence of B-cells/antibodies. Dementia, including its most common form, Alzheimer's disease (AD), is one of the major causes of disability affecting older people, with an estimated 50 million people living with a form of dementia globally. Increased life expectancy is predicted to result in the greatest increase in prevalence in the next decade 1. This is further amplified by unexplained increasing prevalence of dementia at ages between 65 and 80 2. Together, this increases the urgency to understand underlying disease mechanisms and eventually develop effective treatments. Antibodybased therapeutic approaches have been extensively explored, although with limited success when targeting Aβ 3-5. Therefore, current immunotherapeutic developments increasingly focus on alternative targets, in particular the neuronal microtubule-associated protein tau. While known causes of dementia have been identified as genetic mutations 6,7 and traumatic brain injuries 8 , whether endogenous antibody (= autoantibody)-mediated processes contribute to disease onset and progression remains unknown. The microtubule-associated protein tau is the main component of neurofibrillary tangle (NFT) pathology in AD and other dementias. Tau has over 80 predicted phosphorylation sites, many of which are phosphorylated in physiological processes (e.g. brain development 9) and disease 10-12. Phosphorylation of tau leads to changes in conformation, so...

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Mouse models of frontotemporal dementia: A comparison of phenotypes with clinical symptomatology

Cited by 27 publications

References 168 publications

Review: Modelling the pathology and behaviour of frontotemporal dementia

Review: Modelling the pathology and behaviour of frontotemporal dementia

Frontotemporal Dementia: A Clinical Review

Contribution of endogenous antibodies to learning deficits and astrocytosis in human P301S mutant tau transgenic mice

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