Abstract
BackgroundAlzheimer’s disease (AD) is the most common type of dementia, affecting one in eight adults over 65 years of age. The majority of AD cases are sporadic, with unknown etiology, and only 5% of all patients with AD present the familial monogenic form of the disease. In the present study, our aim was to establish an in vitro cell model based on patient-specific human neurons to study the pathomechanism of sporadic AD.MethodsWe compared neurons derived from induced pluripotent stem cell (iPSC) lines of patients with early-onset familial Alzheimer’s disease (fAD), all caused by mutations in the PSEN1 gene; patients with late-onset sporadic Alzheimer’s disease (sAD); and three control individuals without dementia. The iPSC lines were differentiated toward mature cortical neurons, and AD pathological hallmarks were analyzed by RT-qPCR, enzyme-linked immunosorbent assay, and Western blotting methods.ResultsNeurons from patients with fAD and patients with sAD showed increased phosphorylation of TAU protein at all investigated phosphorylation sites. Relative to the control neurons, neurons derived from patients with fAD and patients with sAD exhibited higher levels of extracellular amyloid-β 1–40 (Aβ1–40) and amyloid-β 1–42 (Aβ1–42). However, significantly increased Aβ1–42/Aβ1–40 ratios, which is one of the pathological markers of fAD, were observed only in samples of patients with fAD. Additionally, we detected increased levels of active glycogen synthase kinase 3 β, a physiological kinase of TAU, in neurons derived from AD iPSCs, as well as significant upregulation of amyloid precursor protein (APP) synthesis and APP carboxy-terminal fragment cleavage. Moreover, elevated sensitivity to oxidative stress, as induced by amyloid oligomers or peroxide, was detected in both fAD- and sAD-derived neurons.ConclusionsOn the basis of the experiments we performed, we can conclude there is no evident difference except secreted Aβ1–40 levels in phenotype between fAD and sAD samples. To our knowledge, this is the first study in which the hyperphosphorylation of TAU protein has been compared in fAD and sAD iPSC-derived neurons. Our findings demonstrate that iPSC technology is suitable to model both fAD and sAD and may provide a platform for developing new treatment strategies for these conditions.
Highlights
Alzheimer’s disease (AD) is the most common type of dementia, affecting one in eight adults over 65 years of age
We studied induced pluripotent stem cell (iPSC) clones derived from three patients with familial Alzheimer’s disease (fAD) with mutation in presenilin 1 (PSEN1), four patients with late-onset sporadic Alzheimer’s disease (sAD), and three individuals without dementia as control subjects
The present study shows that particular key disease phenotypes of the most common age-related neurological disorder, AD, can be modeled using patient-specific, Fig. 7 Effect of hydrogen peroxide (H2O2) and amyloid-β1–42 (Aβ1–42) oligomer treatment on neuronal viability. a Viability of induced pluripotent stem cell-derived neurons from control individuals, patients with early-onset familial Alzheimer’s disease, and patients with sporadic Alzheimer’s disease at day 28 of terminal differentiation (TD28) and TD56 after 24 h of treatment with 30 μM H2O2 and 60 μM H2O2. b Neuronal survival of control and Alzheimer’s disease (AD) clones at TD28 and TD56 cultured 24 h in the presence of 5 μM amyloid-β 1–42 (Aβ1–42) oligomer solution
Summary
Alzheimer’s disease (AD) is the most common type of dementia, affecting one in eight adults over 65 years of age. Alzheimer’s disease (AD) is the best characterized among them, and it accounts for 50–60% of all dementia cases [1] This common neurodegenerative disease is clinically characterized by a progressive and gradual cognitive impairment, synapse loss, and substantial loss of neurons in later stages. Most cases of early-onset AD are linked to autosomal dominant inherited mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2). These cases are referred to as familial Alzheimer’s disease (fAD) and are well characterized. There is no cure for AD, and the available medications can only slow down the progression of dementia and slightly improve the quality of life of the patients [3]
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