Intracerebral injection of preformed synthetic tau fibrils initiates widespread tauopathy and neuronal loss in the brains of tau transgenic mice.

Neurofibrillary tangles composed of hyperphosphorylated fibrillized tau are found in numerous tauopathies including Alzheimer's disease. Increasing evidence suggests that tau pathology can be transmitted from cell-to-cell; however the mechanisms involved in the initiation of tau fibrillization and spreading of disease linked to progression of tau pathology are poorly understood. We show here that intracerebral injections of preformed synthetic tau fibrils into the hippocampus or frontal cortex of young tau transgenic mice expressing mutant human P301L tau induces tau hyperphosphorylation and aggregation around the site of injection, as well as a time-dependent propagation of tau pathology to interconnected brain areas distant from the injection site. Furthermore, we show that the tau pathology as a consequence of injection of tau preformed fibrils into the hippocampus induces selective loss of CA1 neurons. Together, our data confirm previous studies on the seeded induction and the spreading of tau pathology in a different tau transgenic mouse model and reveals neuronal loss associated with seeded tau pathology in tau transgenic mouse brain. These results further validate the utility of the tau seeding model in studying disease transmission, and provide a more complete in vivo tauopathy model with associated neurodegeneration which can be used to investigate the mechanisms involved in tau aggregation and spreading, as well as aid in the search for disease modifying treatments for Alzheimer's disease and related tauopathies.

Absence of Uptake and Prion-Like Spreading of Alpha-Synuclein and Tau After Intravitreal Injection of Preformed Fibrils.

Although very different in etiology and symptoms, numerous neurodegenerative diseases can be classified as proteinopathies. More so, evidence indicates that the key misfolded proteins at the basis of different neuropathies might share common mechanisms of propagation. As such, the prion-like spreading of protein aggregates through the neural network is subject of intensive research focus and requires adequate models. Here, we made use of the well-defined architecture and large accessibility of the visual system, of which the retinotopic connections represent a simple route of anterograde signaling and an elegant model to investigate transsynaptic, prion-like spreading. In two independent studies, uptake and seeding of alpha-synuclein and tau were examined after intravitreal injection of preformed fibrils. However, extracellular matrix components in the vitreous space and at the vitreoretinal surface appeared to act as a barrier for the entry of both fibrils into the retina. These results show that further experimental refinement is needed to fully realize the potential of the visual system as a model for studying the molecular and cellular mechanisms of anterograde, transsynaptic spreading of prion-like proteins.

Performance of F2 B6x129 hybrid mice in the Morris water maze, latent inhibition and prepulse inhibition paradigms: Comparison with C57Bl/6J and 129sv inbred mice.

Assessment of cognition and information processing in mice is an important tool in preclinical research that focuses on the development of cognitive enhancing drugs. Analysis of transgenic (TG) and knockout (KO) mice is usually performed on a F2 B6x 129 background. In the present study, we have compared performance of F2 B6x 129 hybrid mice (F2 mice) with that of the two parental inbred strains (C57Bl/6J and 129sv mice), and a wild-type (WT) strain (with a combined B6x 129 background) in three cognitive/information processing paradigms. It was found that the F2 mice outperformed either of the parental strains and provide a control sample with good baseline performance in the Morris water maze (MWM). Reliable deficits could be obtained in learning and memory in this paradigm following injections with scopolamine (0.16 mg/kg) in the F2 mice, which can potentially be used to test effects of reference and novel compounds in order to develop cognitive enhancing drugs. Furthermore, it was shown that the four genotypes showed normal latent inhibition (LI) using the conditioned taste aversion (CTA) paradigm and exhibited no differences in prepulse inhibition (PPI) levels. Following the setup of these procedures in mice, we are now able to compare the effects of gene knockout/mutations used for target validation with results in the present study as a frame of reference.

PDE10A inhibitors stimulate or suppress motor behavior dependent on the relative activation state of the direct and indirect striatal output pathways.

The enzyme phosphodiesterase 10A (PDE10A) regulates the activity of striatal, medium spiny neurons (MSNs), which are divided into a behaviorally stimulating, Gs-coupled D1 receptor-expressing "direct" pathway and a behaviorally suppressant, Gi-coupled D2 receptor-expressing "indirect" pathway. Activating both pathways, PDE10A inhibitors (PDE10AIs) combine functional characteristics of D2 antagonists and D1 agonists. While the effects of PDE10AIs on spontaneous and stimulated behavior have been extensively reported, the present study investigates their effects on suppressed behavior under various conditions of reduced dopaminergic neurotransmission: blockade of D1 receptors with SCH-23390, blockade of D2 receptors with haloperidol, or depletion of dopamine with RO-4-1284 or reserpine. In rats, PDE10AIs displayed relatively low cataleptic activity per se. After blocking D1 receptors, however, they induced pronounced catalepsy at low doses close to those required for inhibition of apomorphine-induced behavior; slightly higher doses resulted in behavioral stimulant effects, counteracting the catalepsy. PDE10AIs also counteracted catalepsy and related behaviors induced by D2 receptor blockade or dopamine depletion; catalepsy was replaced by behavioral stimulant effects under the latter but not the former condition. Similar interactions were observed at the level of locomotion in mice. At doses close to those inhibiting d-amphetamine-induced hyperlocomotion, PDE10AIs reversed hypolocomotion induced by D1 receptor blockade or dopamine depletion but not hypolocomotion induced by D2 receptor blockade. It is concluded that PDE10AIs stimulate or inhibit motor behavior dependent on the relative activation state of the direct and indirect striatal output pathways.

The d-amphetamine-treated Göttingen miniature pig: an animal model for assessing behavioral effects of antipsychotics.

RATIONALE: Rodents are usually used to assess the ability of antipsychotic drugs to antagonize hyperlocomotion induced by dopamine agonists, such as the psychostimulant d-amphetamine. However, the substantial differences between rodents and humans may hinder extrapolation of experimental results to humans. For this reason, we speculated that Göttingen miniature pigs, which show strong physiological and genetic homology with humans, might be a better model for investigating the effects of antipsychotics. To investigate this, we determined whether d-amphetamine induced hyperlocomotion in miniature pigs and whether this effect was reversible by antipsychotics. MATERIALS AND METHODS: d-amphetamine was tested in the dose range of 0.2 to 2.0 mg kg(-1) for its ability to induce hyperactivity in the open field, and the effects of two antipsychotics, haloperidol and risperidone, on amphetamine-induced hyperactivity were examined. RESULTS: d-amphetamine increased open-field activity at 0.2, 0.4, and 0.7 mg kg(-1) s.c. but not at higher doses. The stimulation of open-field activity induced by 0.4 mg kg(-1) s.c. d-amphetamine was antagonized by haloperidol and risperidone (0.01 and 0.04 mg kg(-1) s.c.). CONCLUSION: d-amphetamine-induced hyperlocomotion in miniature pigs may be a useful model for studying the effect of putative antipsychotics.