Implication of MAM in a cellular model of Alzheimer's disease

Alzheimer disease (AD) is one of the most common form of dementia. An hallmark of AD brains is the presence of extracellular plaques mainly composed by the amyloid-? peptide (A?). AD has been associated with aberrant cholesterol, phospholipid, calcium metabolism, and alteration of mitochondrial function. These features of AD have also been related to mitochondria-associated Endoplasmic Reticulum (ER) membranes (MAMs). These structures permit physical interaction between Mitochondria and ER depends on complementary membrane proteins, which tether the two organelles together at specific sites. VDAC, a protein localized at the outer mitochondrial membrane (OMM), forms a complex with GRP75 and IP3R that reside at the ER. The VDAC-GRP75-IP3R complex facilitates the transfer of Ca2+ from the ER to mitochondria. Given the potential relationship between MAM and AD, we explored the possibility that perturbation of MAM function might play a role in AD pathogenesis. Here, we utilized an in vitro AD model (Lan5 neuronal cells treated with A?) in which, through specific fluorescent dyes for mitochondria and ER and the in situ proximity of the ligation assay (PLA), we demonstrated that A? induces MAM dysfunction. Moreover, we determined that the known protective action of insulin against A? insult was also played through the reconstruction of MAM integrity. This data was confirmed by calcium flux analysis