Oxidative stress and altered mitochondrial protein expression in the absence of amyloid-β and tau pathology in iPSC-derived neurons from sporadic Alzheimer's disease patients

Abstract

Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) and increased production of reactive oxygen species (ROS) has been described in postmortem brain samples and animal models. However, these observations were made at a late stage of disease and the inability to examine an early, presymptomatic phase in human neurons impeded our understanding of cause or consequence of mitochondrial dysfunction in AD. We used human induced pluripotent stem cell-derived neuronal cells (iN cells) from sporadic AD (SAD) patients and healthy control subjects (HCS) to show aberrant mitochondrial function in patient-derived cells. We observed that neuronal cultures from some patients produced more ROS and displayed higher levels of DNA damage. Furthermore, patient-derived cells showed increased levels of oxidative phosphorylation chain complexes, whereas mitochondrial fission and fusion proteins were not affected. Surprisingly, these effects neither correlated with Aβ nor phosphorylated and total tau levels. Synaptic protein levels were also unaffected in SAD iN cells. The results of this study give new insights into constitutional metabolic changes in neurons from subjects prone to develop Alzheimer's pathology. They suggest that increased ROS production may have an integral role in the development of sporadic AD prior to the appearance of amyloid and tau pathology.

Modeling Alzheimer’s disease with iPSC-derived brain cells

“…Patient-derived SAD cells often exhibit many of the same phenotypes as cells bearing FAD mutations when differentiated into neurons. In addition to elevated Aβ levels and tau phosphorylation, iPSC-derived neurons from SAD patients can exhibit enlarged endosomes, mitochondrial dysfunction, activation of ER, and oxidative stress pathways, elevated DNA damage as well as increased sensitivity to Aβ toxicity and oxidative stress [54,78,89,110,111]. Altered gene expression, early neuronal differentiation and maturation, as well as perturbed activity of the transcription factor REST have also been observed [112].…”

“…Altered gene expression, early neuronal differentiation and maturation, as well as perturbed activity of the transcription factor REST have also been observed [112]. Importantly, these phenotypes are not observed in cells derived from all SAD patients, reinforcing the genetic heterogeneity of SAD [78,89,102,110,111,113].…”

Cloning of Presenilin 2 cDNA and Construction of Vectors Carrying Effective Mutations in the Pathogenesis of Familial Alzheimer's Disease

“…Alzheimer's disease is categorized in a late-onset, an early-onset, familial type, sporadic type which indicates about 95% of the patients [20]. The genetic factors of early-onset Alzheimer's disease are heterogeneous.…”

Proteomic Analyses of Exothermic Processes in Rat Brain Homogenate

“…A solution of protein standards was used to calibrate the mass scale. The mass spectrometer was externally calibrated with a mixture of angiotensin I, glu-fibrinopeptide B, ACTH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), and ACTH.…”

“…Applying 2D-electrophoresis and Western blot analyses, differential splicing and different phosphorylated tau proteins have been identified [8][9][10][11]. Specific phosphorylation is essential to modulate protein location and protein-protein interactions [12,13].…”