Figure 3.

The organelle interactome in AD. Contact sites between the ER and mitochondria (MAM) were linked to a physical interaction between MFN2 and PSEN2/γ-secretase, while ER-LE/Lys contacts may represent a primary root for organellar disruption through the generation of aggregation-prone Aβ in LE/Lys by PSEN2/γ-secretase. The illustrated observation that lysosomal Ca²⁺ is disrupted in AD supports this hypothesis. Contacts between the ER and the plasma membrane are additionally represented in order to illustrate disruption of Ca²⁺ homeostasis involving the capacitative SOCE mechanism, with a suggested interaction between PSEN1/γ-secretase and STIM1.