Geon The Roles of Microtubules
and Tau Protein in Neuronal Excitability



For over three decades, the evidence that microtubules might play a role in neuronal excitability has been largely ignored. More recently, several groups provided direct evidence for the involvement of microtubule-associated protein Tau in excitability. This paper shows that the Tau-induced hyperexcitability could play a central role in tauopathy which includes Alzheimer's disease, Huntington's disease and Tau-positive frontotemporal dementia. These neurodegenerative disorders are characterized by elevated total and/or 4R-Tau level. According to the Microtubule Model for Excitability (MTME) proposed in Paper 1, elevation of total and/or 4R-Tau promotes dissociation of microtubules from the membrane of axon initial segment (AIS), thereby increasing excitability. The microtubule-bound Tau proteins in AIS are vulnerable to phosphorylation by protein kinases, particularly GSK-3β. Hence, the tauopathy exhibits Tau pathology (Tau hyperphosphorylation and neurofibrillary tangles).


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