Deciphering neuronal dysfunction in Tau pathology
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A hallmark feature of Alzheimer's disease pathology is the presence of neurofibrillary tangles (NFTs), which are intracellular aggregates of conformationally abnormal and hyperphosphorylated tau. Tau function is important in modulating microtubules stability in the axon of neurons and in the processes of oligodendrocytes. The presence of NFTs in the forebrain is associated with impairments of cognitive function, but the significance of the accumulation of NFTs for neuronal/glial and cognitive function is still obscure. In this thesis I tested the hypothesis that NFTs disrupt synaptic transmission and plasticity, leading to memory deficits and cognitive malfunction by performing behavioral tests, electrophysiological experiments, in combination with western blotting and immunocytochemical techniques, in the htau mouse model of tau pathology. The data presented in this thesis show that htau mice have age-dependent cognitive and physiological impairments which preceded neurodegeneration. 12-month-old htau (older) mice with moderate tau pathology, but not 4-month-old mice with early stage tau pathology, presented cognitive deficits in spatial memory and object recognition memory tasks. In older htau mice, cognitive behavioral deficits were accompanied by electrophysiological changes in the CA3 to CA1 synapse. Older htau mice show reduction in the probability of neurotransmitter release from presynaptic terminals, reduced axonal excitability and inability of the fibers to follow high-frequency activity. These changes correlated with tau accumulation in oligodendrocytes and reduction in the essential myelin components, myelin basic protein. We also investigated the involvement of the JNK pathway in tau phosphorylation, as well as potential JNK substrates, such as microtubule associated protein 2 (MAP2), and AMPA receptors. Axonal impairment and myelin abnormalities were associated with phosphor-JNK upregulation, increased phosphorylation and total levels of MAP2. Moreover, there was a downregulation of the GluR2 subunit of AMPARs, which may have significant implications for synaptic transmission and plasticity. Taken together, our results suggest that tau pathology underlies an age-dependent learning impairment possibly through disruption of oligodendrocytes and neuronal functions. We propose that tau abnormalities play a central role in dementia, suggesting that tau could be a promising therapeutic target to prevent or reduce the progression of AD and other tauopathies.
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