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: 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
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ABSTRACT: Many different approaches to treating tauopathies are currently being explored, with a few compounds already in clinical development (including small molecules such as anti-aggregation compound LMTX and active vaccines AADvac1 and ACI-35). This review aims to summarize the status of the clinical candidates and to highlight the emerging areas of research that hold promise for drug development. Tau is post-translationally modified in several different ways (phosphorylated, acetylated ,glycosylated and truncated). The extent of these modifications can be manipulated to influence tau aggregation state and pathogenesis and the enzymes involved provide tractable targets for drug intervention. In addition, modulation of tau expression levels is an attractive therapeutic approach. Finally, the recently described prion-like spreading of tau between cells opens up novel avenues from the tau drug development perspective. The review compares the merits of small-molecule and antibody-based therapies and emphasizes the need for amenable clinical biomarkers for drug development, particularly PET imaging.Neuropathology and Applied Neurobiology 10/2014; 41(1). DOI:10.1111/nan.12192 · 4.97 Impact Factor