|8. Ankyrin-G Level Is Reduced in
APP/PS1 Transgenic Mice
Ankyrin-G plays a critical role as the "anchor" for various proteins to the membrane at the axon initial segment (AIS), which is a short axon segment proximal to the cell body (Buffington and Rasband, 2011; Hsu et al., 2014). AIS contains high density of voltage-gated sodium and potassium channels, in particular the non-inactivating sodium channel, Nav1.6 (O'Brien and Meisler, 2013). Since action potential is initiated at AIS, opening of the Nav1.6 channel has a significant impact on neuronal firing.
Ankyrin-G (encoded by the ANK3 gene) is implicated in all kinds of mental disorders, including Alzheimer's disease (Morgan et al., 2008), attention deficit hyperactivity disorder (Iqbal et al., 2013), autism (Bi et al., 2012), bipolar disorder (Schulze et al., 2009), posttraumatic stress (Logue et al., 2013) and schizophrenia (Athanasiu et al., 2010). Compelling evidence suggests that mental disorders arise from abnormal functional connectivity due to impairment in long range synchronization (see The Role of Ankyrin-G in Mental Disorders). The Microtubule Model for Excitability (see Chapter 9) was originally proposed to explain the underlying mechanism for long range synchronization. This model posits that neuronal excitability could be regulated by Ankyrin-G, microtubules and the Tau protein.
As discussed in Chapter 7, the APP/PS1 transgenic mice exhibit hyperexcitability. Very interestingly, Ankyrin-G level in the transgenic mice is decreased. More specifically, the APP/PS1 expression up-regulates a microRNA, miR-342-5p, which in turn down-regulates the expression of Ankyrin-G (Sun et al., 2014). Injection of Ankyrin-G into the APP transgenic mice reduces β-amyloid pathology (Santuccione et al., 2013).
According to the Microtubule Model for Excitability, Ankyrin-G may attenuate excitability by anchoring microtubules near the AIS membrane and reducing the open probability of the Nav1.6 channel in the membrane. Decreased Ankyrin-G level will enhance excitability. The Tau protein, being a microtubule-associated protein, may interfere with the binding between Ankyrin-G and microtubules, thereby modulating neuronal excitability. The 4-repeat Tau binds to the microtubule much stronger than the 3-repeat Tau (see Chapter 5). Hence, the two Tau isoforms can have differential effects on excitability, which could play a key role in AD, as well as other tauopathies (see Chapter 10).
Author: Frank Lee