The Role of the Endoplasmic Reticulum-Mitochondria Cross-Talk in Alzheimer's Disease

What is it about?

A common feature of neurodegenerative diseases is the formation of misfolded, mostly enzyme resistant proteins. These substances may form toxic assemblies according to the current concept of the neurodegenerative diseases. Overlapping of the misfolded proteins is typical in these disorders. The formation of misfolded proteins and toxic aggregates point to a common pathway of these disorders: failure in normal protein folding in the ER as a consequence of ER-stress and mitochondrial energy production. Alzheimer's disease (AD) is a rather heterogeneous, multifactorial disorder with wide clinical heterogeneity and is classified into several subtypes. In AD the processing of the amyloid precursor protein (APP) and formation of toxic Aβ structures occur intraneuronally. Aβ affects both ER and mitochondria and disturbs Ca2+-homeostasis of the cells. Mitochondrial dysfunction is one of the main pathological events in AD. Mitochondria accumulate Aβ derived from the ER/Golgi or from the mitochondria-associated ER-membranes (MAM). Free radicals, oxidative stress and increasing Ca2+-concentration in mitochondria cause decreased ATP production. Mitochondrial dynamic and trafficking are also altered as a result of Aβ toxicity. Synaptic mitochondria show a very high vulnerability. Depletion of Ca2+ level in the ER results in dysfunction of protein folding and evokes unfolded protein response (UPR), and affects also mitochondria. MAM may play special role in the ER-mitochondria cross talk. Mitochondria themselves (using mitochondria-targeting antioxidants such as MitoQ) could be a special target for AD treatment. Another targets are the UPR cascade proteins (PERK, IRE1, ATF6) and receptors involved in Ca2+ -level stabilization of the ER (Ryr, IP3R).

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Why is it important?

Mitochondrial dysfunction is also observed in AD. Unfolded protein induced stress occurs in mitochondria (MT) leading to neurodegeneration. The ER and mitochondria form a highly dynamic interconnected network in generation of Ca2+-signal and maintaining Ca2+ homeostasis. Particularly mitochondria-associated ER-membranes (MAMs) may play an important role in the induction of AD. Very recently it was proposed that the multi-protein molecular network of MAM, involving key proteins from the MT and ER, is important for fundamental cell functions. Disruption of the molecular interactions in ER-MT common protein network is in conjunction with serious neurodegenerative diseases such as AD. Understanding the etiology and pathomechanism of NDDs requires systematic studies on ER, MT, Ca2+-dyshomeostasis, the ER-MT interface and cross talk. Our aim was to review the literature on the role of ER and mitochondria as well as the ER-MT cross talk and Ca2+-cycle in the etiology and pathophysiology of AD.

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