Alzheimer  >   16. Spreading of Tau Pathology

It has been well established that the Tau pathology propagates along anatomically connected neural networks (Liu et al., 2012), but its underlying mechanism remains elusive. The prion-like hypothesis posits that the pathology spreading could be mediated by Tau aggregates which are released from affected neurons to the extracellular space and then taken up by adjacent cells (Frost and Diamond, 2010). This hypothesis is supported by two findings: (1) extracellular short Tau fibrils, but not long filaments, can be internalized (Wu et al., 2013), and (2) injection of Tau fibrils into a mouse brain region leads to Tau pathology in anatomically connected regions (Guo et al., 2016). However, there is so far no convincing evidence that Tau aggregates can be secreted from a viable neuron (Hasegawa, 2016; Goedert and Spillantini, 2017).

In contrast, evidence indicates that extracellular monomeric Tau protein is sufficient to initiate the spread of Tau pathology. Not only can monomeric Tau be internalized (Wauters et al., 2016), it can also be released from neurons in full-length or truncated form. The secretion of full-length Tau is facilitated by phosphorylation, while the truncated Tau must contain the N-terminal half (Kim et al., 2010; Plouffe et al., 2012). Monomeric Tau is released from presynaptic terminals (Sokolow et al., 2015), consistent with the synaptically connected spreading pattern. Furthermore, the secretion of monomeric Tau increases with increasing neural activity (Pooler et al., 2013; Yamada et al., 2014; Wu et al., 2016). Hence, hyperexcitability should promote Tau release into the extracellular space (Mohamed et al., 2017).

In the extracellular space, the pathological Tau species (phosphorylated and/or truncated) have the propensity to form aggregates. However, the aggregation state is not required for pathology spreading. As discussed in Chapter 6, Tau toxicity depends on the exposure of "phosphatase-activating domain" (PAD). As long as the PAD is exposed, Tau or its fragment may spread pathology, whether it is monomeric or in an aggregate.

Spreading of Hyperactive GSK-3β

The exposed PAD may activates protein phosphatase 1 (PP1), which in tun will activate GSK-3β (Chapter 6). Hyperactive GSK-3β may cause Tau hyperphosphorylation, resulting in Tau pathology. Therefore, as the extracellular PAD-exposed Tau species are internalized by a neuron, they may cause hyperactive GSK-3β within the newly affected neuron. The hyperactive GSK-3β can then phosphorylate Tau protein in this neuron, leading to Tau pathology. In this manner, the spreading of Tau pathology is essentially the spreading of hyperactive GSK-3β mediated by PAD-exposed Tau species (Figure 1).


Figure 1. A model for the mechanism of Tau pathology spreading which is essentially the spreading of hyperactive GSK-3β mediated by PAD-exposed Tau species.


Author: Frank Lee
First published: August 13, 2019