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Background: Alzheimer'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. Methods: We 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. Results: Neurons 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-ß 1-40 (Aß1-40) and amyloid-ß 1-42 (Aß1-42). However, significantly increased Aß1-42/Aß1-40 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 ß, 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. Conclusions: On the basis of the experiments we performed, we can conclude there is no evident difference except secreted Aß1-40 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. [ABSTRACT FROM AUTHOR]

Aging is characterized by a chronic low-grade sterile inflammation dubbed as inflammaging, which in part originates from accumulating cellular debris. These, acting as danger signals with many intrinsic factors such as cytokines, are sensed by a network of pattern recognition receptors and other cognate receptors, leading to the activation of inflammasomes. Due to the inflammasome activity-dependent increase in the levels of pro-inflammatory interleukins (IL-1β, IL-18), inflammation is initiated, resulting in tissue injury in various organs, the brain and the spinal cord included. Similarly, in age-related diseases of the central nervous system (CNS), inflammasome activation is a prominent moment, in which cells of the neurovascular unit occupy a significant position. In this review, we discuss the inflammatory changes in normal aging and summarize the current knowledge on the role of inflammasomes and contributing mechanisms in common CNS diseases, namely Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and stroke, all of which occur more frequently with aging. [ABSTRACT FROM AUTHOR]

Abstract: Creutzfeldt–Jakob (CJD) and Alzheimer disease (AD) are accompanied by selective neuronal loss in the brain. We examined the regional and subcellular immunolocalization of ubiquitin, proteasomal subunits, and the heat-shock protein Hsp72 in control, CJD, and AD cases. In control and non-affected areas of disease cases, 20S proteasomes, 19S regulatory subunits, S6a, S6b, and S10b exhibit mainly cytoplasmic, whereas S4 and S7 show predominantly nuclear localization. The intensity of immunostaining for ubiquitin, proteasomal subunits, and Hsp72 varies in different anatomical regions both in disease and control brains. Areas with weaker immunolabeling correspond to affected areas in CJD and AD. In disease cases, antibodies for 20S, S4, S6b, S7, and ubiquitin intensely immunolabel neuronal nuclei of vulnerable cells in affected areas. Our results suggest that the ubiquitin–proteasome system takes part in the pathogenesis of neurodegeneration. Ubiquitin, Hsp72, and proteasomal ATPases possibly play a role in protecting certain neuronal populations in CJD and AD. [Copyright &y& Elsevier]