Figure 6:

Illustration of the tau missorting sequence. (a) In healthy neurons, tau (green) is (a1) localized to the axon at levels three times greater than the soma and dendrites. (a2) While tau is largely excluded from dendritic spines, the small amount of tau located in the soma and dendrites may enter the spines and facilitate synaptic strengthening during LTP induction. After pathogenic insults from multiple disease mechanisms, (b3) tau is redistributed into the soma and dendrites of neurons due to the breakdown of tau sorting mechanisms or tau modifications leading to evasion of those mechanisms. However, (b4) dendritic tau does not mislocalize to dendritic spines. Once in the dendritic shaft, (c5) phosphorylation, truncation, and acetylation of tau lead to further mislocalization into the dendritic spines. (c6) Tau, redistributed in the soma and dendrites, begins to aggregate to form tau inclusions. Somatodendritic tau redistribution leads to (d7) dendritic spine loss, and (d8) retraction of neuritic processes. (d9) Tau mislocalization to dendritic spines leads to AMPA receptor signaling deficits due to LTD-like AMPA receptor internalization and the failure of LTP induction mechanisms. (e) Ultimately, somatodendritic tau contributes to cytotoxicity and cell death. Notably, overt tau pathology and neuron loss have been shown to be dissociated, even in the presence of pro-apoptotic signals, suggesting that cell death may result from the contribution of an independent pathway.