Perturbed mitochondria-ER contacts in live neurons modelling Alzheimer's disease amyloid pathology

Abstract

Mitochondria-ER contacts (MERC) upregulation was suggested as an underlying mechanism in Alzheimer`s disease (AD). Dynamic analysis of live neurons modelling AD-like amyloid pathology showed loosened mitochondria-ER apposition providing a novel perturbation of MERC axis in AD.

ER-mitochondria contact sites in neurodegeneration: genetic screening approaches to investigate novel disease mechanisms

“…Exposure of oligomeric Aβ in primary hippocampal neurones increases MERCS and alters Ca 2v homoeostasis [62], while familial or sporadic AD patient fibroblasts have increased ER-mitochondria coupling and MERCS function, including phospholipid and cholesterol metabolism [61]. However, dynamic and ultrastructural analysis of hippocampal neurones from AD rat models showed a decrease in MERCS, correlating with a reduction in lipid metabolism and specific alterations in mitochondria lipids [63]. In Drosophila, forced expression of an artificial linker, that increases MERCS in vivo, rescues locomotion and prolongs the survival of AD models [64].…”

MERCs. The Novel Assistant to Neurotransmission?

“…Despite the fact that the MAM proteome is rather conservative in various cell types ( Wang X. et al, 2018 ), the length of mitochondria-ER contacts may differ depending on the specific cell type ( Giacomello and Pellegrini, 2016 ). For example, in mouse fibroblast cell cultures, 2.25% of the mitochondrial membrane is in close contact (<20 nm) with the ER ( Cosson et al, 2012 ), in HeLa cells – 5–20% ( Rizzuto et al, 1998 ), about 7% in neuronal cultures ( Martino Adami et al, 2019 ), and about 10% in lymphoma cells ( Csordás et al, 2006 ). Researchers observed the ER completely covering the mitochondrion around the area of its division ( Friedman et al, 2011 ).…”

Mitochondrial Supercomplexes: Physiological Organization and Dysregulation in Age-Related Neurodegenerative Disorders

“…The total number of lipids detected was 106 and 12 were significantly different in Tg as compared to control rats. Among them, a 60% decrement in mitochondrial CL and PE was observed ( 32 ). These results allow us to speculate that at early stages of AD pathology, there could be a disassembly of the SCs of neuronal mitochondria due to alteration in CL and PE synthesis, which in turn may promote neuronal bioenergetics dysfunction, a characteristic feature of this neurological disorder ( 33 – 36 ).…”