|Alzheimer > 7. Tau Protein Increases Neuronal Excitability|
Neuronal hyperexcitability is an early sign of Alzheimer's disease (AD) (Dickerson et al., 2005; Putcha et al., 2011; Vossel et al., 2013; Vossel et al., 2017; Sánchez et al., 2018). Since the generation of action potentials arises from the opening of ion channels, neuronal excitability usually depends on ion channels. However, mounting evidence suggests that elevated total or 4-repeat (4R) Tau protein increases excitability. As discussed in Chapter 6, Tau protein is a central player in AD. Therefore, the Tau-mediated hyperexcitability should play a key role in the pathogenesis of AD. This chapter will present evidence for the involvement of Tau in hyperexcitability. Its underlying mechanism will be discussed in subsequent chapters.
Evidence from Animal Models
Evidence from Human Tauopathy
Tauopathy is a class of neurodegenerative diseases that exhibit Tau pathology (Tau hyperphosphorylation and neurofibrillary tangles). These diseases are associated with elevated total and/or 4R-Tau level as well as hyperexcitability.
Hyperexcitability Increases Calpain Activity
Neuronal firing is accompanied with Ca2+ influx through various types of calcium channels and Ca2+-conducting NMDA receptors. Thus, hyperexcitability can lead to high Ca2+ concentration within the neuron. It has been well documented that calcium dysregulation is critical for neurodegeneration (Mattson, 2007). Ca2+ overload may increase the activities of GSK-3β and cyclin dependent kinase 5 (Cdk5) by activating calpain (Figure 7-1), which is a Ca2+-dependent protease that cleaves proteins (Ferreira, 2012).
GSK-3β and Cdk5 are the major protein kinases capable of phosphorylating Tau at multiple sites (Wang et al., 2007). In a normal free Tau, both N and C termini fold back to form a "paperclip conformation". Phosphorylation at S199/S202/T205 moves the N-terminal domain away from the C-terminal domain while phosphorylation at S396/S404 moves the C-terminal domain away from the repeat domain. In either case, PAD is exposed. GSK-3β and Cdk5 target all of these sites (Wang et al., 2007; Noble et al., 2003). As proposed in Chapter 6, PAD exposure could be a major mechanism underlying Tau pathology. However, Tau proteins phosphorylated at S202/T205 or S396/S404 are selectively targeted for degradation (Dickey et al., 2006). Therefore, the real purpose of PAD exposure during hyperexcitability is likely to reduce Tau level, thereby attenuating hyperexcitability. It is the failure of the degradation system that causes the disease.
Author: Frank Lee