Figure 7: Model of Aβ’s mechanisms of action.

The upper part illustrates a hypothetical time course showing short- and long-term effects of Aβ in our experimental conditions. The lower part shows a cartoon of the combined effects of extracellular and intracellular Aβ. Extracellular Aβ, which is kept in contact with the cell surface, activates RhoA and its downstream targets ROCK and myosin II, increasing actin retrograde flow. Internalized soluble Aβ inhibits HDAC6 inducing an increase in the acetylation of tubulin heterodimers. In parallel, tau is also hyperacetylated due to HDAC6 inhibition, and MT instability is favoured. The alterations of the dynamics of both cytoskeletal elements induce growth cone collapse and neurite retraction. MT instability in the AIS in particular leads to dispersion of ankG (brown ovals) and of Na⁺ channels (yellow channels) outside the AIS, and to missorting of tau in dendrites, with ensuing loss of neuronal polarity and inefficient AP firing.