Modulation of the endoplasmic reticulum–mitochondria interface in Alzheimer’s disease and related models

TLDR

Mitochondria‑associated ER membranes (MAMs) are lipid‑raft–like ER subdomains that mediate lipid synthesis, calcium homeostasis, and apoptosis, and their dysfunction has been implicated in Alzheimer’s disease. This study aimed to determine how Alzheimer’s disease alters ER‑mitochondria interactions in the brain. Using human AD brain tissue, AD mouse models, and neuronal cell lines, the authors quantified MAM distribution, examined the IP3R‑VDAC bridging complex, and measured protein expression, contact points, and mitochondrial calcium levels. They found that MAMs are uniformly distributed in neurons, that PFR2 and σ1 receptor knockdown causes degeneration, that MAM‑associated proteins are up‑regulated in AD brain and APP Swe/Lon mice before plaque formation, and that amyloid β nanomolar concentrations increase IP3R and VDAC expression, ER‑mitochondria contacts, and mitochondrial calcium, underscoring a key role for ER‑mitochondria crosstalk in AD pathology.

Abstract

It is well-established that subcompartments of endoplasmic reticulum (ER) are in physical contact with the mitochondria. These lipid raft-like regions of ER are referred to as mitochondria-associated ER membranes (MAMs), and they play an important role in, for example, lipid synthesis, calcium homeostasis, and apoptotic signaling. Perturbation of MAM function has previously been suggested in Alzheimer's disease (AD) as shown in fibroblasts from AD patients and a neuroblastoma cell line containing familial presenilin-2 AD mutation. The effect of AD pathogenesis on the ER-mitochondria interplay in the brain has so far remained unknown. Here, we studied ER-mitochondria contacts in human AD brain and related AD mouse and neuronal cell models. We found uniform distribution of MAM in neurons. Phosphofurin acidic cluster sorting protein-2 and σ1 receptor, two MAM-associated proteins, were shown to be essential for neuronal survival, because siRNA knockdown resulted in degeneration. Up-regulated MAM-associated proteins were found in the AD brain and amyloid precursor protein (APP)Swe/Lon mouse model, in which up-regulation was observed before the appearance of plaques. By studying an ER-mitochondria bridging complex, inositol-1,4,5-triphosphate receptor-voltage-dependent anion channel, we revealed that nanomolar concentrations of amyloid β-peptide increased inositol-1,4,5-triphosphate receptor and voltage-dependent anion channel protein expression and elevated the number of ER-mitochondria contact points and mitochondrial calcium concentrations. Our data suggest an important role of ER-mitochondria contacts and cross-talk in AD pathology.