|Alzheimer > 9. How Can Tau Protein Increase Excitability?|
Chapter 7 has presented compelling evidence that elevated total and/or four-repeat (4R) Tau protein increase neuronal excitability. Chapter 8 proposes Microtubule Model for Excitability (MTME) to explain why Ankyrin-G is also implicated in excitability. Tau is a well-established microtubule-associated protein. This chapter will show that the Tau-mediated hyperexcitability can be explained by MTME.
Tau Prevents Ankyrin-G/Microtubule Binding
According to MTME, the excitability of pyramidal neurons is largely dependent on the electric field from microtubule fascicles acting on the voltage sensor (S4 segment) of sodium channels in the axon initial segment (AIS). Most AIS sodium channels would be closed when the microtubule fascicle associates with the membrane via Ankyrin-G and EB1/3. The open probability of AIS sodium channels will increase sharply as the microtubule fascicle dissociates from the membrane due to disruption of the binding between fascicle and Ankyrin-G. The Tau protein interacts with not only microtubules, but also EB1/3 (Sayas et al., 2015). Therefore, Tau could be recruited to the binding sites between microtubules and EB1/3. These sites are the anchor points that link microtubules to the membrane. As Tau proteins are recruited to anchor points, they will prevent the binding between Ankyrin-G and microtubule fascicles, thereby increasing excitability (Figure 9-1).
The above mechanism predicts that elevated total Tau level should increase excitability by promoting dissociation of microtubule fascicles from the membrane. The 4R-Tau contains more microtubule binding repeats than the 3R-Tau. Thus, 4R-Tau has stronger binding affinity to microtubules than 3R-Tau (Bunker et al., 2004). Therefore, 4R-Tau can prevent Ankyrin-G/microtubule binding more effectively than 3R-Tau. This explains why elevated total and/or 4R-Tau increase excitability. The mechanism also agrees with the finding that Tau phosphorylation attenuates excitability.
Tau phosphorylation Attenuates Excitability
Phosphorylation is a process that adds a negatively charged phosphate group (PO43−) to a protein. Therefore, phosphorylation of the Tau protein generally reduces its binding affinity to microtubules, particularly at sites serine-262 and threonine-231, which have strong impact on the Tau-microtubule binding (Sengupta et al., 1998). According to the above mechanism, detachment of Tau protein from microtubules at the AIS should attenuate neuronal excitability, thereby reducing excitotoxicity, including the deleterious effects of hyperactive GSK-3β. This prediction agrees with the finding that at the early stage of AD, increased phosphorylation within or near Tau's microtubule binding domain correlates with reduced levels of neuronal excitability, suggesting that Tau phosphorylation on these sites represents a compensatory mechanism that mediates neuroprotection against hyperexcitability (Mondragón-Rodríguez et al., 2018).
Comparison Between Tauopathy and Synucleinopathy
Tauopathy is defined as a class of neurodegenerative diseases that exhibit Tau pathology (Tau hyperphosphorylation and neurofibrillary tangles). Hyperactive GSK-3β is the major protein kinase that causes Tau pathology (Chapter 6). In tauopathy, hyperactive GSK-3β could be caused by elevated total and 4R-Tau level. As illustrated in Figure 9-1, GSK-3β may phosphorylate Tau proteins in AIS, thereby resulting in Tau pathology. The Tau proteins in other axonal regions are relatively inaccessible to GSK-3β because they are tightly packed in a microtubule network.
Parkinson's disease (PD) is a typical synucleinopathy that exhibits α-synuclein pathology (Appendix C) with little Tau pathology compared to progressive supranuclear palsy (Schonhaut et al., 2017) which is a tauopathy with symptoms resembling PD. miR-132 is down-regulated in tauopathy, but up-regulated in PD (Chapter 11). Therefore, unlike tauopathy, the total and 4R-Tau levels are reduced in PD. This may explain why PD exhibits little Tau pathology even though it is also associated with hyperactive GSK-3β. Instead, the α-synuclein level is elevated in PD. As a result, the hyperactive GSK-3β would phosphorylate mainly α-synuclein, leading to the hallmark of synucleinopathy - Lewy bodies - where approximately 90% of α-synuclein are phosphorylated at the target site of GSK-3β: serine-129.
Author: Frank Lee