Alzheimer’s disease (AD) is the most common cause of dementia and the sixth cause of death in the world, constituting a major health problem for aging societies. This disease is a neurodegenerative continuum with well-established pathology hallmarks, namely the deposition of amyloid-β (Aβ) peptides in extracellular plaques and intracellular hyperphosphorylated forms of the microtubule associated protein tau forming neurofibrillary tangles (NFTs), accompanied by neuronal and synaptic loss. Interestingly, patients who will eventually develop AD manifest brain pathology decades before clinical symptoms appear. Among all the proposed pathogenic mechanisms to understand the etiology of Alzheimer’s disease (AD), increased oxidative stress seems to be a robust and early disease feature where many of those hypotheses converge.
Pathogenic Mechanism | Main Finding | Cellular Type | Lineage | References |
---|---|---|---|---|
Amyloid/Tau | Platelets from AD patients reproduce the increased amyloidogenic processing of AβPP | Platelets | Non-neuronal | [61] |
Amyloid/Tau | AD platelets harbor increased levels of a higher molecular weight tau isoform | Platelets | Non-neuronal | [62] |
Amyloid/Tau | Alteration of AβPP, BACE, and ADAM 10 levels in early stages of the disease | Platelets | Non-neuronal | [63][64][65] |
Amyloid/Tau | It is suggested a decreased non-amyloidogenic processing of AβPP by a lack of nicastrin mRNA expression in samples obtained from AD patients | Lymphocytes | Non-neuronal | [66] |
Amyloid/Tau | Altered balance between Aβ-oligomers and PKCε levels in AD. Loss of PKCε-mediated inhibition of Aβ |
Fibroblasts | Non-neuronal | [67] |
Amyloid/Tau | Higher Aβ42/Aβ40 ratio compared to control cells | PSEN1 iPSC-derived neural progenitors |
Neuronal | [68] |
Amyloid/Tau | Mutation alters the initial cleavage site of γ-secretase, resulting in an increased generation of Aβ42, in addition to an increase in the levels of total and phosphorylated tau | Neuron-derived iPSCs from patients harboring the London FAD AβPP mutation V717I |
Neuronal | [69] |
Amyloid/Tau | Oligomeric forms of canonical Aβ impairs synaptic plasticity |
Cortical neurons from three genetic forms of AD —PSEN1 L113_I114insT, AβPP duplication (AβPPDp), and Ts21— generated from iPSCs | Neuronal | [70] |
Amyloid/Tau | Increase in the content and changes in the subcellular distribution of t-tau and p-tau in cells from AD patients compared to controls | Non-invasively isolated ONPs | Neuronal | [9] |
Mitochondria | Compromise of mitochondrial COX from AD patients |
Platelets | Non-neuronal | [71] |
Mitochondria | Platelets isolated from AD patients show decreased ATP levels | Platelets | Non-neuronal | [72] |
Mitochondria | AD lymphocytes exhibit impairment of total OXPHOS capacity | Lymphocytes | Non-neuronal | [73] |
Mitochondria | AD skin fibroblasts show increased production of CO2 and reduced oxygen uptake suggesting that mitochondrial electron transport chain might be compromised |
Fibroblasts | Non-neuronal | [74] |
Mitochondria | AD fibroblasts present reduction in mitochondrial length and a dysfunctional mitochondrial bioenergetics profile | Fibroblasts | Non-neuronal | [75] |
Mitochondria | SAD fibroblasts exhibit aged mitochondria, and their recycling process is impaired | Fibroblasts | Non-neuronal | [76] |
Mitochondria | Patient-derived cells show increased levels of oxidative phosphorylation chain complexes | Human induced pluripotent stem cell-derived neuronal cells (iN cells) from SAD patients |
Neuronal | [77] |
Mitochondria | Mitophagy failure as a consequence of lysosomal dysfunction |
iPSC-derived neurons from FAD1 patients harboring PSEN1 A246E mutation | Neuronal | [78] |
Mitochondria | Neurons exhibit defective mitochondrial axonal transport |
iPSC-derived neurons from an AD patient carrying AβPP -V715M mutation | Neuronal | [79] |
Oxidative Stress | Increased activity of the antioxidant enzyme catalase in probable AD patients | Erythrocytes | Non-neuronal | [80] |
Oxidative Stress | Increased production and content of thiobarbituric acid-reactive substances (TBARS), superoxide dismutase (SOD), and nitric oxide synthase (NOS) |
Erythrocytes and Platelets | Non-neuronal | [81] |
Oxidative Stress | Increase in the content of the unfolded version of p53 as well as reduced SOD activity | Peripheral blood mononuclear cells (PBMCs) | Non-neuronal | [82] |
Oxidative Stress | Exacerbated response to NFKB pathway | PBMCs | Non-neuronal | [83] |
Oxidative Stress | Increased ROS production in response to H2O2 | PBMCs | Non-neuronal | [59] |
Oxidative Stress | AD lymphocytes were more prone to cell death after a H2O2 challenge | Lymphocytes | Non-neuronal | [84] |
Oxidative Stress | Reduced antioxidant capacity of FAD lymphocytes and fibroblasts together with increased lipid peroxidation on their plasma membrane | Lymphocytes and Fibroblasts | Non-neuronal | [85] |
Oxidative Stress | Aβ peptides were better internalized and generated greater oxidative damage in FAD fibroblasts | Fibroblasts | Non-neuronal | [86] |
Oxidative Stress | Aβ peptide caused a higher increase in the oxidation of HSP60 | Fibroblasts | Non-neuronal | [87] |
Oxidative Stress | Reduction in the levels of Vimentin in samples from AD patients | iPSCs-derived neurons from AD patient | Neuronal | [58] |
Oxidative Stress | Increased levels of hydroxynonenal, Nɛ-(carboxymethyl)lysine), and heme oxygenase-1 in samples from AD patients | Biopsy-derived ONPs | Neuronal | [24] |
Oxidative Stress | Increased susceptibility to oxidative-stress-induced cell death | Biopsy-derived ONPs | Neuronal | [25] |
ER-Stress | Impaired ER Ca2+ and ER stress in PBMCs from MCIs and mild AD patients | PBMCs | Non-neuronal | [88] |
ER-Stress | Accumulation of Aβ oligomers induced ER and oxidative stress | iPSC-derived neural cells from a patient carrying APP-E693Δ mutation and a sporadic AD patient | Neuronal | [89] |
ER-Stress | Aβ-S8C dimer triggers an ER stress response more prominent in AD neuronal cultures where several genes from the UPR were upregulated | iPSC-derived neuronal cultures carrying the AD-associated TREM2 R47H variant | Neuronal | [90] |
ER-Stress | Accumulation of Aβ oligomers in iPSC-derived neurons from AD patients leads to increased ER stress |
iPSC-derived neurons from patients with an AβPP-E693Δ mutation | Neuronal | [91] |
This entry is adapted from the peer-reviewed paper 10.3390/ijms22126311