Age-appropriate cognition and subtle dopamine-independent motor deficits in aged Tau knockout mice
ABSTRACT The microtubule-associated protein tau is expressed throughout the nervous system, most highly in neurons but also in glial cells. Its functions in adult and aging mammals remain to be defined. Previous studies in mouse models found either protective or detrimental effects of genetic tau ablation. Though tau ablation prevented synaptic, network, and cognitive dysfunctions in several models of Alzheimer's disease and made mice more resistant to epileptic seizures, a recent study described a parkinsonian phenotype in aging Tau knockout mice. Here we tested cognition and motor functions in Tau(+/+), Tau(+/-), and Tau(-/-) mice at approximately 1 and 2 years of age. Tau ablation did not impair cognition and caused only minor motor deficits that were much more subtle than those associated with the aging process. Tau ablation caused a mild increase in body weight, which correlated with and might have contributed to some of the motor deficits. However, tau ablation did not cause significant dopaminergic impairments, and dopamine treatment did not improve the motor deficits, suggesting that they do not reflect extrapyramidal dysfunction.
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ABSTRACT: Because reduction of the microtubule-associated protein Tau has beneficial effects in mouse models of Alzheimer's disease and epilepsy, we wanted to determine whether this strategy can also improve the outcome of mild traumatic brain injury (TBI). We adapted a mild frontal impact model of TBI for wildtype C57Bl/6J mice and characterized the behavioral deficits it causes in these animals. The Barnes maze, Y maze, contextual and cued fear conditioning, elevated plus maze, open field, balance beam, and forced swim test were used to assess different behavioral functions. Magnetic resonance imaging (MRI, 7 Tesla) and histological analysis of brain sections were used to look for neuropathological alterations. We also compared the functional effects of this TBI model and of controlled cortical impact in mice with two, one or no Tau alleles. Repeated (2-hit), but not single (1-hit), mild frontal impact impaired spatial learning and memory in wildtype mice as determined by testing of mice in the Barnes maze one month after the injury. Locomotor activity, anxiety, depression and fear related behaviors did not differ between injured and sham-injured mice. MRI imaging did not reveal focal injury or mass lesions shortly after the injury. Complete ablation or partial reduction of tau prevented deficits in spatial learning and memory after repeated mild frontal impact. Complete tau ablation also showed a trend towards protection after a single controlled cortical impact. Complete or partial reduction of tau also reduced the level of axonopathy in the corpus callosum after repeated mild frontal impact. Tau promotes or enables the development of learning and memory deficits and of axonopathy after mild TBI, and tau reduction counteracts these adverse effects.PLoS ONE 12/2014; 9(12):e115765. DOI:10.1371/journal.pone.0115765 · 3.53 Impact Factor
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ABSTRACT: The accumulation of alpha-synuclein aggregates is the hallmark of Parkinson's disease, and more generally of synucleinopathies. The accumulation of tau aggregates however is classically found in the brains of patients with dementia, and this type of neuropathological feature specifically defines the tauopathies. Nevertheless, in numerous cases alpha-synuclein positive inclusions are also described in tauopathies and vice versa, suggesting a co-existence or crosstalk of these proteinopathies. Interestingly, alpha-synuclein and tau share striking common characteristics suggesting that they may work in concord. Tau and alpha-synuclein are both partially unfolded proteins that can form toxic oligomers and abnormal intracellular aggregates under pathological conditions. Furthermore, mutations in either are responsible for severe dominant familial neurodegeneration. Moreover, tau and alpha-synuclein appear to promote the fibrillization and solubility of each other in vitro and in vivo. This suggests that interactions between tau and alpha-synuclein form a deleterious feed-forward loop essential for the development and spreading of neurodegeneration. Here, we review the recent literature with respect to elucidating the possible links between alpha-synuclein and tau.Molecular Neurodegeneration 10/2014; 9(1):43. DOI:10.1186/1750-1326-9-43 · 5.29 Impact Factor
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ABSTRACT: Iron accumulation and tau protein deposition are pathological features of Alzheimer's (AD) and Parkinson's diseases (PD). Soluble tau protein is lower in affected regions of these diseases, and we previously reported that tau knockout mice display motor and cognitive behavioral abnormities, brain atrophy, neuronal death in substantia nigra, and iron accumulation in the brain that all emerged between 6 and 12 months of age. This argues for a loss of tau function in AD and PD. We also showed that treatment with the moderate iron chelator, clioquinol (CQ) restored iron levels and prevented neuronal atrophy and attendant behavioral decline in 12 month old tau KO mice when commenced prior to the onset of deterioration (6 months). However, therapies for AD and PD will need to treat the disease once it is already manifest. So, in the current study, we tested whether CQ could also rescue the phenotype of mice with a developed phenotype. We found that 5 months treatment of symptomatic (13 month old) tau KO mice with CQ increased nigral tyrosine hydroxylase phosphorylation (which induces activity) and reversed the motor deficits. Treatment also reversed cognitive deficits and raised BDNF levels in hippocampus, which was accompanied by attenuated brain atrophy, and reduced iron content in the brain. These data raise the possibility that lowering brain iron levels in symptomatic patients could reverse neuronal atrophy and improve brain function, possibly by elevating neurotrophins. Copyright © 2015. Published by Elsevier Inc.Neurobiology of Disease 03/2015; DOI:10.1016/j.nbd.2015.03.015 · 5.20 Impact Factor