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

  • Hyperexcitability was observed in mice expressing mutant (P301L)Tau protein (Crimins et al., 2012).
  • The genomic mouse DNA containing mutant (N296H) Tau gene expressed more 4R-Tau protein, resulting in hyperactivity (Wobs et al., 2017).
  • Increasing 4R-Tau expression without change to total Tau in human Tau-expressing mice induced pathological changes by either predisposing mice to seizure activity or exacerbating hyperexcitability (Schoch et al., 2016).
  • Genetic removal of the Tau gene attenuates neuronal network hyperexcitability in mice and Drosophila (Holth et al., 2013).
  • Antisense oligonucleotides that selectively decrease endogenous Tau expression in adult mice protect against seizures (DeVos et al., 2013).

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.

  • Alzheimer's disease. In healthy brains, the expression level of 3R-Tau is comparable across all different brain regions studied, including the hippocampus, entorhinal cortex (EC), frontal cortex, occipital-temporal cortex, parietal-temporal cortex, the striatum, olfactory bulb and the cerebellum. However, the expression levels of total and 4R-Tau are the highest in EC (Hu et al., 2017). This may explain why AD begins in EC, specifically in lateral EC (Khan et al., 2014).
  • Huntington's disease is a genetic disorder due to expansion of the CAG repeat within the huntingtin gene. The genetic abnormality increases 4R-Tau (Fernández-Nogales et al., 2014). Seizure often occurs in the juvenile form of Huntington's disease (Cloud et al., 2012).
  • Progressive supranuclear palsy is a 4R tauopathy (Katsuse et al., 2003). It increases the risk for seizures (Nygaard et al., 1989).
  • Corticobasal degeneration is another 4R tauopathy (Katsuse et al., 2003). It is characterized by hyperexcitability of the motor cortex (Lu et al., 1998; Nardone et al., 2019).

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).


Figure 7-1. Regulation of GSK-3 and Cdk5 by calpain.
(A) In the inactive form, GSK-3 contains an inhibitory domain. Calpain may remove this inhibitory domain to activate GSK-3 (Goñi-Oliver et al., 2007).
(B) Cdk5 is normally activated by binding to the protein p35. Calpain may cleave p35 to generate p25, forming a hyperactive Cdk5/p25 complex (Kimura et al., 2014).

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
First published: June 27, 2019