Hippocampal tauopathy in tau transgenic mice coincides with impaired hippocampus-dependent learning and memory, and attenuated late-phase long-term depression of synaptic transmission

Laboratory of Biological Psychology, Department of Psychology, Catholic University of Leuven, Belgium.
Neurobiology of Learning and Memory (Impact Factor: 3.65). 12/2010; 95(3):296-304. DOI: 10.1016/j.nlm.2010.12.005
Source: PubMed

ABSTRACT We evaluated various forms of hippocampus-dependent learning and memory, and hippocampal synaptic plasticity in THY-Tau22 transgenic mice, a murine tauopathy model that expresses double-mutated 4-repeat human tau, and shows neuropathological tau hyperphosphorylation and aggregation throughout the brain. Focussing on hippocampus, immunohistochemical studies in aged THY-Tau22 mice revealed prominent hyper- and abnormal phosphorylation of tau in CA1 region, and an increase in glial fibrillary acidic protein (GFAP) in hippocampus, but without signs of neuronal loss. These mice displayed spatial, social, and contextual learning and memory defects that could not be reduced to subtle neuromotor disability. The behavioral defects coincided with changes in hippocampal synaptic functioning and plasticity as measured in paired-pulse and novel long-term depression protocols. These results indicate that hippocampal tauopathy without neuronal cell loss can impair neural and behavioral plasticity, and further show that transgenic mice, such as the THY-Tau22 strain, might be useful for preclinical research on tauopathy pathogenesis and possible treatment.

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Available from: Ann Van der Jeugd, Feb 05, 2014
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    • "Importantly, miR-125b injection causes increased phospho-tau levels in vivo confirming our earlier findings in cultured neurons (Fig 6). Fly and mouse models of tauopathies show impaired learning and memory, which is accompanied by tau tangle formation in mice, while drosophila models predominantly display neurotoxicity (Van der Jeugd et al, 2011; Gistelinck et al, 2012). Strikingly, overexpression of miR-125b is slightly neurotoxic in primary neurons, while blocking miR-125b action with miR-125b TuD is neuroprotective (Supplementary Fig S3). "
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    ABSTRACT: Sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but no clear disease-initiating mechanism is known. Aβ deposits and neuronal tangles composed of hyperphosphorylated tau are characteristic for AD. Here, we analyze the contribution of microRNA-125b (miR-125b), which is elevated in AD. In primary neurons, overexpression of miR-125b causes tau hyperphosphorylation and an upregulation of p35, cdk5, and p44/42-MAPK signaling. In parallel, the phosphatases DUSP6 and PPP1CA and the anti-apoptotic factor Bcl-W are downregulated as direct targets of miR-125b. Knockdown of these phosphatases induces tau hyperphosphorylation, and overexpression of PPP1CA and Bcl-W prevents miR-125b-induced tau phosphorylation, suggesting that they mediate the effects of miR-125b on tau. Conversely, suppression of miR-125b in neurons by tough decoys reduces tau phosphorylation and kinase expression/activity. Injecting miR-125b into the hippocampus of mice impairs associative learning and is accompanied by downregulation of Bcl-W, DUSP6, and PPP1CA, resulting in increased tau phosphorylation in vivo. Importantly, DUSP6 and PPP1CA are also reduced in AD brains. These data implicate miR-125b in the pathogenesis of AD by promoting pathological tau phosphorylation.
    The EMBO Journal 07/2014; 33(15). DOI:10.15252/embj.201387576 · 10.43 Impact Factor
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    • "Interestingly, deletion of tau did not affect NMDA-dependent LTD which was found previously to be impaired in THY-Tau22 transgenic mice which express double-mutated human 4-repeat Tau (Van der Jeugd et al., 2010). In conclusion, the complex phenotype of tau KO mice observed in our study indicates a major physiological role of tau in certain forms of learning and synaptic plasticity which adds an important facet to its well-described pathologic functions. "
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    ABSTRACT: Tau has been implicated in the organization, stabilization, and dynamics of microtubules. In Alzheimer's disease and more than 20 neurologic disorders tau missorting, hyperphosphorylation, and aggregation is a hallmark. They are collectively referred to as tauopathies. Although the impact of human tauopathies on cognitive processes has been explored in transgenic mouse models, the functional consequences of tau deletion on cognition are far less investigated. Here, we subjected tau knock-out (KO) mice to a battery of neurocognitive, behavioral, and electrophysiological tests. Although KO and wild-type mice were indistinguishable in motor abilities, exploratory and anxiety behavior, KO mice showed impaired contextual and cued fear conditioning. In contrast, extensive spatial learning in the water maze resulted in better performance of KO mice during acquisition. In electrophysiological experiments, basal synaptic transmission and paired-pulse facilitation in the hippocampal CA1-region were unchanged. Interestingly, deletion of tau resulted in severe deficits in long-term potentiation but not long-term depression. Our results suggest a role of tau in certain cognitive functions and implicate long-term potentiation as the relevant physiological substrate.
    Neurobiology of Aging 06/2014; 35(11). DOI:10.1016/j.neurobiolaging.2014.05.005 · 5.01 Impact Factor
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    • "These observations have led some authors to the hypothesis that Tau pathology could be the major cause of cognitive decline in humans (Wilcock and Esiri, 1982; Delaere et al., 1989; Arriagada et al., 1992; Duyckaerts et al., 1997, 1998; Gomez-Isla et al., 1997; Delacourte et al., 2002; Giannakopoulos et al., 2003; Guillozet et al., 2003; Bretteville and Planel, 2008). These findings are in accordance with numerous animal studies showing significant impairment of cognitive functions, synaptic dysfunctions, as well as altered hippocampal synaptic plasticity in different transgenic mouse models of Tauopathies (Polydoro et al., 2009; Hoover et al., 2010; Van Der Jeugd et al., 2011; Burnouf et al., 2013). "
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    ABSTRACT: The neuropathological hallmarks of Alzheimer's disease (AD) include senile plaques of β-amyloid (Aβ) peptides (a cleavage product of the Amyloid Precursor Protein, or APP) and neurofibrillary tangles (NFT) of hyperphosphorylated Tau protein assembled in paired helical filaments (PHF). NFT pathology is important since it correlates with the degree of cognitive impairment in AD. Only a small proportion of AD is due to genetic variants, whereas the large majority of cases (~99%) is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease. Insulin dysfunction, manifested by diabetes mellitus (DM) might be such factor, as there is extensive data from epidemiological studies suggesting that DM is associated with an increased relative risk for AD. Type 1 diabetes (T1DM) and type 2 diabetes (T2DM) are known to affect multiple cognitive functions in patients. In this context, understanding the effects of diabetes on Tau pathogenesis is important since Tau pathology show a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment. Here, we reviewed preclinical studies that link insulin dysfunction to Tau protein pathogenesis, one of the major pathological hallmarks of AD. We found more than 30 studies reporting Tau phosphorylation in a mouse or rat model of insulin dysfunction. We also payed attention to potential sources of artifacts, such as hypothermia and anesthesia, that were demonstrated to results in Tau hyperphosphorylation and could major confounding experimental factors. We found that very few studies reported the temperature of the animals, and only a handful did not use anesthesia. Overall, most published studies showed that insulin dysfunction can promote Tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia.
    Frontiers in Cellular Neuroscience 02/2014; 8:22. DOI:10.3389/fncel.2014.00022 · 4.29 Impact Factor
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