Maria Ankarcrona

A large number of physiological processes are perturbed in Alzheimer’s disease (AD). These include damage to mitochondria and the endoplasmic reticulum (ER), disruption to axonal transport, perturbations to Ca2+ homeostasis and lipid metabolism, defective autophagy and finally inflammatory responses. The biological conundrum is how so many apparently disparate physiological processes are damaged collectively. Recently, work from us and others, has focused on damage to mitochondria-ER contacts (MERCS) in AD

this is because they regulate all these damaged physiological processes.  We have identified mechanisms by which these contacts form and are regulated and shown that disrupted ER-mitochondria signaling is linked to neurodegenerative disease. Here we aim to take this work a step further and our current hypothesis is that correcting damaged ER-mitochondria signaling will correct many other downstream damaged features of AD and other neurodegenerative disorders and therefore have broad therapeutic value. The primary objectives are to identify the link between impaired ER-mitochondria interplay and onset of inflammation and synaptic dysfunction in AD. We will use novel mouse models for AD and perform in vitro (primary neurons and microglia) and in vivo experiments. Using RNA silencing techniques we will modulate the structure and function of MERCS and investigate the effects on inflammasome formation, mitochondrial function and synaptic signalling.