Age-appropriate cognition and subtle dopamine-independent motor deficits in aged Tau knockout mice
Biochemistry, Cellular and Molecular Biology Graduate Program, Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Neurobiology of aging
(Impact Factor: 5.01).
01/2013; 34(6). DOI: 10.1016/j.neurobiolaging.2012.12.003
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.
Available from: David I Finkelstein
- "The heterozygotes did not express significant deficits but there was a trend to increase in the time to finish parameter compared to background-matched controls (One-way ANOVA with post hoc test for linear trend, for Bl6, p = 0.017; for Bl6/129sv, p = 0.019). There was no correlation between the mouse body weight and time to turn in the Pole test, similar to the results published by Morris et al.
 (For all Bl6 mice, r2 = 0.087, p = 0.135; For all Bl6/129sv mice, r2 = 0.015, p = 0.569; "
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We recently reported that Parkinsonian and dementia phenotypes emerge between 7-12 months of age in tau-/- mice on a Bl6/129sv mixed background. These observations were partially replicated by another group using pure Bl6 background tau-/- mice, but notably they did not observe a cognitive phenotype. A third group using Bl6 background tau-/- mice found cognitive impairment at 20-months of age.
To reconcile the observations, here we considered the genetic, dietary and environmental variables in both studies, and performed an extended set of behavioral studies on 12-month old tau+/+, tau+/-, and tau-/- mice comparing Bl6/129sv to Bl6 backgrounds. We found that tau-/- in both backgrounds exhibited reduced tyrosine hydroxylase-positive nigral neuron and impaired motor function in all assays used, which was ameliorated by oral treatment with L-DOPA, and not confounded by changes in body weight. Tau-/- in the C57BL6/SV129 background exhibited deficits in the Y-maze cognition task, but the mice on the Bl6 background did not.
These results validate our previous report on the neurodegenerative phenotypes of aged tau-/- mice, and show that genetic background may impact the extent of cognitive impairment in these mice. Therefore excessive lowering of tau should be avoided in therapeutic strategies for AD.
Molecular Neurodegeneration 08/2014; 9(1):29. DOI:10.1186/1750-1326-9-29 · 6.56 Impact Factor
Available from: Dominic P D'Agostino
- "It is also feasible that the Tg4510 mice have a difference in basal metabolism. In agreement with this observation, Morris et al.  found that the ablation of tau (Tau-/-) caused weight gain in middle-aged mice. This is suggestive of tau playing a possible role in the hypermetabolic phenotype encountered in this study. "
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ABSTRACT: Dietary manipulations are increasingly viewed as possible approaches to treating neurodegenerative diseases. Previous studies suggest that Alzheimer's disease (AD) patients present an energy imbalance with brain hypometabolism and mitochondrial deficits. Ketogenic diets (KDs), widely investigated in the treatment and prevention of seizures, have been suggested to bypass metabolic deficits present in AD brain by providing ketone bodies as an alternative fuel to neurons. We investigated the effects of a ketogenic diet in two transgenic mouse lines. Five months old APP/PS1 (a model of amyloid deposition) and Tg4510 (a model of tau deposition) mice were offered either a ketogenic or a control (NIH-31) diet for 3 months. Body weight and food intake were monitored throughout the experiment, and blood was collected at 4 weeks and 4 months for ketone and glucose assessments. Both lines of transgenic mice weighed less than nontransgenic mice, yet, surprisingly, had elevated food intake. The ketogenic diet did not affect these differences in body weight or food consumption. Behavioral testing during the last two weeks of treatment found that mice offered KD performed significantly better on the rotarod compared to mice on the control diet independent of genotype. In the open field test, both transgenic mouse lines presented increased locomotor activity compared to nontransgenic, age-matched controls, and this effect was not influenced by KD. The radial arm water maze identified learning deficits in both transgenic lines with no significant differences between diets. Tissue measures of amyloid, tau, astroglial and microglial markers in transgenic lines showed no differences between animals fed the control or the ketogenic diet. These data suggest that ketogenic diets may play an important role in enhancing motor performance in mice, but have minimal impact on the phenotype of murine models of amyloid or tau deposition.
PLoS ONE 09/2013; 8(9):e75713. DOI:10.1371/journal.pone.0075713 · 3.23 Impact Factor
Available from: David Blum
- "Prior studies involving behavioral endpoints in mutant tau transgenic mice have revealed cognitive impairments in some tasks               . Here, a crosssectional design was used to avoid the possible influence of multiple testing on individual mice. "
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ABSTRACT: Age-related cognitive decline and neurodegenerative diseases are a growing challenge for society. Accumulation of tau pathology has been proposed to partially contribute to these impairments. This study provides a behavioral characterization during aging of transgenic mice bearing tau mutations. THY-Tau22 mice were evaluated at ages wherein tau neuropathology in this transgenic mouse model is low (3-4 months), moderate (6-7 months), or extensive (>9 months). Spatial memory was found to be impaired only after 9 months of age in THY-Tau22 mice, whereas non-spatial memory was affected as early as 6 months, appearing to offer an opportunity for assessing potential therapeutic agents in attenuating or preventing tauopathies through modulation of tau kinetics.
Journal of Alzheimer's disease: JAD 07/2013; 37(4). DOI:10.3233/JAD-130110 · 4.15 Impact Factor
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