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 β-amyloid (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 mitochondriaassociated
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 ERmitochondria
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).
Keywords: β-amyloid, endoplasmic reticulum, mitochondria-associated endoplasmic reticulum-membrane, mitochondria malfunction,
synaptic mitochondria, unfolded protein response.
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