Environmental Enrichment Rescues Functional Deficit and Alters Neuroinflammation in a Transgenic Model of Tauopathy.

Alzheimer's disease (AD) is the most frequent neurodegenerative disorder, affecting over 44 million people worldwide. There are no effective pharmaco-therapeutic options for prevention and treatment of AD. Non-pharmacological approaches may help patients suffering from AD to significantly ameliorate disease progression. In this study, we exposed a transgenic rat model (tg) of human tauopathy to enriched environment for 3 months. Behavioral testing at 6 months of age revealed improvement in functional deficits of tg rats reared under enriched conditions, while sedentary tg rats remained severely impaired. Interestingly, enriched environment did not reduce tau pathology. Analysis of neurotrophic factors revealed an increase of nerve growth factor (NGF) levels in the hippocampus of both enriched groups (tg and non-tg rats), reflecting a known effect of enriched environment on the hippocampal formation. On the contrary, NGF levels decreased markedly in the brainstem of enriched groups. The non-pharmacological treatment also reduced levels of tissue inhibitor of metalloproteinase 1 in the brainstem of transgenic rats. Expression analysis of inflammatory pathways revealed upregulation of microglial markers, such as MHC class II and Cd74, whereas levels of pro-inflammatory cytokines remained unaffected by enriched environment. Our results demonstrate that exposure to enriched environment can rescue functional impairment in tau transgenic rats without reducing tau pathology. We speculate that non-pharmacological treatment modulates the immune response to pathological tau protein inclusions, and thus reduces the damage caused by neuroinflammation.

CSF phospho-tau correlates with behavioural decline and brain insoluble phospho-tau levels in a rat model of tauopathy.

The aim of the present study was to identify the relationship between progressive neurobehavioural decline and phospho-tau levels (p-tau(181)) in the cerebrospinal fluid (CSF) and the brain in transgenic rats expressing human truncated tau protein. Behavioural analyses, as quantified using the NeuroScale scoring method, revealed that the transgenic rats fell into two main groups based on the baseline behavioural functioning: (1) mild neurobehavioural impairment (MNI, score 3.3-26) and (2) severe neurobehavioural impairment (SNI, score 36-44). SNI transgenic rats showed a significant increase in brain sarkosyl insoluble p-tau(181) when compared to their MNI counterparts. In order to determine whether CSF phospho-tau reflects the behavioural decline and increase in sarkosyl insoluble tau in the brain, p-tau(181) was measured in the CSF in a longitudinal study. The study showed a significant increase in CSF p-tau(181) during the progression of the disease from MNI to SNI. Moreover, increased levels of p-tau(181) in CSF correlated with an increase in the sarkosyl insoluble p-tau(181) levels in the brain. The increase in the CSF level of p-tau(181) during progressive behavioural decline suggests that it may represent a useful surrogate biomarker for preclinical drug development and a potential surrogate endpoint for clinical trials of disease-modifying therapy for Alzheimer's disease and related human tauopathies.

Improved behavioral response as a valid biomarker for drug screening program in transgenic rodent models of tauopathies.

Neurodegenerative tauopathies are defined as a group of dementia and movement disorders characterized by prominent filamentous tau inclusions and degeneration located within certain brain regions. Their common sign is a presence of proteinaceous aggregates composed of hyperphosphorylated and truncated tau proteins. The molecular mechanisms of the disease still remain unresolved, therefore transgenic organisms displaying tau-related neurodegenerative cascade have been created to allow decoding of individual pathways involved in human pathological conditions. Moreover, use of transgenic model organisms enables the application of potential therapeutic approaches. The expression of mutated or misfolded tau as a transgene in vivo leads to significant alteration of neurobehavioral features of experimental animal, therefore detailed classification of behavioral phenotype become one of the first crucial analyses, while it functionally correlates with central nervous system impairment. Currently, two major types of behavioral impairment have been described in transgenic rodent models of tauopathies, (1) progressive motor impairment associated with muscular weakness and premature death and (2) age-related impairment of cognitive functions attended with unaffected motor status. Up to the present, only transgenic models displaying motor impairment were successfully applied into the drug trials targeting misfolded tau protein, despite their behavioral inconsistence with clinical profile of progressive human tauopathy. The aim of this study was, therefore, to summarize the pros and cons of used transgenic rodent models mimicking human tauopathies in connection with development of therapeutic strategies.

Misfolded tau protein and disease modifying pathways in transgenic rodent models of human tauopathies.

Human tauopathies represent a heterogeneous group of neurodegenerative disorders such as Alzheimer's disease (AD) that are characterized by the presence of intracellular accumulations of abnormal filaments of protein tau. Presently, AD poses an increasing public health concern, because it affects nearly 2% of the population in industrialized countries and the number of patients is expected to increase threefold within the next 50 years. Therefore, the identification of disease modifying pathways that will lead to the development of novel therapeutic approaches targeting downstream molecular events of the tauopathy is of paramount importance. In order to identify factors that may exacerbate or inhibit the disease phenotype a number of genetically modified rodent models reproducing key clinical, histopathological and molecular hallmarks of human tauopathies were developed. Current tau transgenic rodent models express as a transgene either an individual or all six human wild-type tau isoforms, mutant tau linked to FTDP-17, or structurally modified tau species derived from AD. In this review we will provide an up-to-date account of various facets of the tau neurodegenerative cascade with a special emphasis on the evolution of neurofibrillary tangles, neuronal death and neuroinflammation.

NeuroScale, the battery of behavioral tests with novel scoring system for phenotyping of transgenic rat model of tauopathy.

We have previously shown that transgenic rats expressing misfolded tau protein developed neurofibrillary tangles and axonal degeneration in the brain and spinal cord, which led to impairment of sensorimotor and neuromuscular functions. To quantify neurobehavioral phenotype of the transgenic rats we have designed a testing protocol and a novel scoring system - NeuroScale - that reliably reflects progression of functional impairment of transgenic rats. NeuroScale consists of three variants of beam walking test with different sensitivity and a rapid neuromuscular and neurological examination, where animal performance is evaluated and scored according to a pre-defined rating scale. The range of the rating scale was developed to increase homogeneity of the collected behavioral data without lowering sensitivity of the testing methods. Finally, all awarded points were summed up to obtain a complete quantitative behavioral readout, the NeuroScale score, from animals under investigation. Increase in the NeuroScale score faithfully mirrored disease progression and allowed statistically significant discrimination (p<0.001) between behavioral responses of transgenic and control animals during the whole disease process. The method was suitable for a high-throughput test whereby an experienced operator can examine up to 60 rats per day. We show that this multi-test battery with novel sensitive scoring system - NeuroScale - represents a rapid, simple to perform, high throughput method for quantitative evaluation of behavioral phenotype of transgenic rats that could serve as a valuable primary read-out for in vivo validation of therapeutic agents.

Truncated tau expression levels determine life span of a rat model of tauopathy without causing neuronal loss or correlating with terminal neurofibrillary tangle load.

We have previously demonstrated in a transgenic rat model of tauopathy that human misfolded truncated tau derived from Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo. We employed this model to investigate the impact of truncated tau expression levels on life span, neuronal loss and the final load of neurofibrillary tangles (NFTs) in transgenic rats. Two independent transgenic lines (SHR72, SHR318), that display different expression levels of truncated tau, were utilized in this study. We found that transgene expression levels in the brain of SHR72 rats were 44% higher than in SHR318 rats and that truncated tau protein levels determined the survival rate of transgenic rats. The line with higher expression levels of truncated tau (SHR72) showed decreased median survival (222.5 days) when compared with the line with lower expression (SHR318; 294.5 days). Interestingly, NFT loads (total NFT/total neurons) were very similar in terminal stages of disease in both transgenic lines (SHR72 - 10.9%; SHR318 - 11.6%), despite significantly different expression levels of truncated tau. Moreover, mean neuron numbers in the hippocampus (CA1-3) and brain stem (gigantocellular reticular nucleus) in the two transgenic rat strains in the terminal stages of disease were similar, and did not differ significantly from those observed in age-matched non-transgenic controls. These findings suggest that the expression levels of misfolded truncated tau determine the life span in a transgenic rat model of tauopathy without causing neuronal loss or correlating with terminal NFT load.