Killing Me Softly: Connotations to Unfolded Protein Response and Oxidative Stress in Alzheimer's Disease

Abstract

This review is focused on the possible causes of mitochondrial dysfunction in AD, underlying molecular mechanisms of this malfunction, possible causes and known consequences of APP, Aβ, and hyperphosphorylated tau presence in mitochondria, and the contribution of altered lipid metabolism (nonsterol isoprenoids) to pathological processes leading to increased formation and accumulation of the aforementioned hallmarks of AD. Abnormal protein folding and unfolded protein response seem to be the outcomes of impaired glycosylation due to metabolic disturbances in geranylgeraniol intermediary metabolism. The origin and consecutive fate of APP, Aβ, and tau are emphasized on intracellular trafficking apparently influenced by inaccurate posttranslational modifications. We hypothesize that incorrect intracellular processing of APP determines protein translocation to mitochondria in AD. Similarly, without obvious reasons, the passage of Aβ and tau to mitochondria is observed. APP targeted to mitochondria blocks the activity of protein translocase complex resulting in poor import of proteins central to oxidative phosphorylation. Besides, APP, Aβ, and neurofibrillary tangles of tau directly or indirectly impair mitochondrial biochemistry and bioenergetics, with concomitant generation of oxidative/nitrosative stress. Limited protective mechanisms are inadequate to prevent the free radical-mediated lesions. Finally, neuronal loss is observed in AD-affected brains typically by pathologic apoptosis.

Figure 1

A diagram of amyloid precursor protein (APP) processing pathway. The transmembrane protein APP (membrane indicated in blue) can be processed by two pathways: the nonamyloidogenic α-secretase pathway and the amyloidogenic β-secretase pathway. In the nonamyloidogenic pathway, α-secretase cleaves in the middle of the β-amyloid (Aβ) region (red) to release the soluble APP-fragment sAPP-α. The APP C-terminal fragment 83 (APP-CTF83, αCTF) is then cleaved by γ-secretase to release the APP intracellular domain (AICD) and P3 fragment. In the amyloidogenic pathway, β-secretase cleaves APP to produce the soluble fragment sAPP-β. APP-CTF99 (βCTF) is then cleaved by γ-secretase to produce Aβ ₄₀, Aβ ₄₂, and AICD. Adopted from [179].

Figure 2

ER stress triggered by misfolded proteins in several neurodegenerative diseases. Abnormal conformations of the proteins APP, Aβ, and tau are implicated in the pathogenesis of AD. Alterations in the function of ER chaperones and UPR-related components, ERAD, ER/Golgi trafficking, and ER-to-mitochondria Ca²⁺ transfer have been suggested as underlying mechanisms of ER stress triggered by these disease-associated proteins. These proteins can accumulate and aggregate at the ER and their stable interaction with ER chaperones such as GRP78/BiP and PDI may trap ER chaperones, altering protein folding with concomitant ER stress. In addition, these proteins can lead to the oxidative modification of the active site of PDIs by nitrosylation leading to their enzymatic inactivation. Furthermore, some of these proteins alter the activity of the UPR stress sensors (IRE1α, PERK, and ATF6) as well as the activity/levels of downstream signaling mediators and transcription factors, including cleaved ATF6, ATF4, and spliced XBP1. As a result, genes implicated in autophagy and ERAD, antioxidant response, ER chaperones, and organelle's biosynthesis are upregulated. Moreover, these proteins block the exit of vesicles from the ER and alter the trafficking between ER and Golgi of properly folded proteins. The cellular responses controlled by UPR transcription factors, including the modulation of autophagy mediated degradation of protein aggregates, become compromised. Disease-related proteins can also interact with ERAD components, precluding the translocation of ERAD substrates from the ER to the cytosol, leading to the accumulation of abnormally folded proteins at the ER. Finally, Ca²⁺ released from the ER, mainly through the IP₃R, and its transfer to mitochondria can be impaired in the presence of disease-related proteins leading to mitochondrial Ca²⁺ overload and activation of apoptotic cell death pathways. AD: Alzheimer's disease; ATF6: activating transcription factor 6; ATF4: activating transcription factor 4; ER: endoplasmic reticulum; ERAD: endoplasmic-reticulum-associated protein degradation; IP₃R: inositol triphosphate receptor; IRE1α: inositol-requiring enzyme 1 alpha; PERK: protein kinase R- (PKR-) like ER kinase; UPR: unfolded protein response; XBP1: Xbox binding protein 1. Adopted from [67].

Figure 3

Amyloid-β-related mitochondrial impairment. Mitochondria were found to be the target for amyloid-β (Aβ), which interacts with several proteins, leading to mitochondrial dysfunction. Indeed, Aβ was found in the outer mitochondrial membrane (OMM) and inner mitochondrial membrane (IMM) as well as in the matrix. The interaction of Aβ with the OMM affects the transport of nuclear-encoded mitochondrial proteins, such as subunits of the electron transport chain complex IV, into the organelle via the translocase of the outer membrane (TOM) import machinery. Moreover, Aβ disturbs the activity of several enzymes, such as pyruvate dehydrogenase (PDH) and oxoglutarate dehydrogenase (OGDH), decreasing NADH reduction, and the electron transport chain enzyme complex IV, reducing the amount of hydrogen that is translocated from the matrix to the intermembrane space (IMS), thus impairing the mitochondrial membrane potential (MMP). Taken together, these events cause abnormal mitochondrial electron activities, leading to decreased complex V activity and so to a drop in ATP levels, in addition to increasing reactive oxygen species (ROS) generation. Moreover, ROS induce peroxidation of several mitochondrial macromolecules, such as mitochondrial DNA (mtDNA) and mitochondrial lipids, contributing to mitochondrial impairment in the mitochondrial matrix. The complex of Aβ bound to binding alcohol dehydrogenase (ABAD) impairs the binding of NAD⁺ to ABAD, changes mitochondrial membrane permeability, and reduces activities of respiratory enzymes, inducing further ROS production and leading to mitochondrial failure. Aβ binding also activates Fis1 (fission protein) and promotes increased mitochondrial fragmentation; this increased mitochondrial fragmentation produces defective mitochondria that ultimately damage neurons. Furthermore, Aβ binding to cyclophilin D (CypD) enhances the protein translocation to the inner membrane, favouring the opening of the mitochondrial permeability transition pore, formed by the adenine nucleotide translocator (ANT) and voltage-dependent anion channels (VDACs). Cyt c: cytochrome c; DLP1: dynamin-like protein 1; PDH: pyruvate dehydrogenase; ProAp: proapoptotic factors; SOD: superoxide dismutase; TCA: tricarboxylic acid; TIM: translocase of the inner membrane. Adopted from [14].