Figure 6.

Concept model for the role of the APP-talin mediated mechanocoupling at the synapse in maintaining mechano-homeostasis, and how dyshomeostasis would lead to wholesale synaptic changes. (a) In a healthy synapse, the basal levels of mechanical forces across the synapse are balanced to establish mechanical homeostasis. Each synaptic stimulation event would lead to a transient increase in tension that would alter the switch patterns and update the synapse, before mechanical homeostasis is reestablished. APP, as part of the mechanocoupling of the synapse, would help to maintain the synchronization of the system as altered mechanics or imbalance would lead to APP-processing-driven feedback mechanisms that reinstate homeostasis. (b) In AD, this mechanical feedback mechanism would be defective, and misprocessing of APP would occur, accelerating the loss of mechanohomeostasis, leading to inappropriate force loading on the remaining cytosketal couplings and production of the toxic Aβ42 species. This loss of mechanical homeostasis would propagate through the two neurons spreading throughout the neuronal circuits as the entire systems mechanical synchronization is lost.