Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting more than 47.5 million people worldwide. Metabolic impairments are common hallmarks of AD, and amyloid-β (Aβ) peptide and hyperphosphorylated tau protein—the two foremost histopathological signs of AD—have been implicated in mitochondrial dysfunction. Many neurodegenerative disorders, including AD, show excessive amounts of mis-/unfolded proteins leading to an activation of the unfolded protein response (UPR). In the present study, we aimed to characterize the link between ER stress and bioenergetics defects under normal condition (human SH-SY5Y neuroblastoma cells: control cells) or under pathological AD condition [SH-SY5Y cells overexpressing either the human amyloid precursor protein (APP) or mutant tau (P301L)]. More specifically, we measured UPR gene expression, cell viability, and bioenergetics parameters, such as ATP production and mitochondrial membrane potential (MMP) in basal condition and after an induced ER stress by thapsigargin. We detected highly activated UPR and dysregulated bioenergetics in basal condition in both AD cellular models. Strikingly, acute-induced ER stress increased the activity of the UPR in both AD cellular models, leading to up-regulation of apoptotic pathways, and further dysregulated mitochondrial function.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting more than 47.5 million people worldwide and will certainly gain more attention in the coming years [1, 2]
We investigated the effect of overexpression of the two AD hallmark proteins, amyloid-β and hyperphosphorylated tau, on the activity of the unfolded protein response (UPR), bioenergetics, and cell viability in basal condition and after acute ER stress induced by thapsigargin in the following cellular models of AD: SH-SY5Y neuroblastoma cells overexpressing amyloid precursor protein (APP) leading to increased Aβ or the mutant form of tau protein (P301L) leading to hyperphosphorylated tau, compared to control cells
To assess whether the presence of two hallmark proteins of AD, APP/Aβ, or tau have per se an influence on the UPR, the regulation of gene expression activity of 84 UPR genes was measured in Mock, APP, P301L, and WT Tau cells using quantitative real-time PCR
Summary
AD is a progressive neurodegenerative disorder affecting more than 47.5 million people worldwide and will certainly gain more attention in the coming years [1, 2]. There are two types of AD: the sporadic form and the familial form. The sporadic form is the most common type and patients show their first behavioural abnormalities starting at 65 years [3]. The cause of the sporadic form remains unknown. They are few cases (1–6%), where the onset of the disease starts at early age (between 35 and 65 years) [3]. Onset cases are often genetically inherited and, termed familial AD (FAD). The early onset is driven by selectively declarative memory loss, followed by fading of cognitive abilities such as language skills, problem solving, and visuospatial perception [4, 5]. From a histopathological point of view, AD is characterized by the presence of amyloid-β
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