ER stress and unfolded protein response in amyotrophic lateral sclerosis—a controversial role of protein disulphide isomerase

Accumulation of proteins in aberrant conformation occurs in many neurodegenerative diseases. Furthermore, dysfunctions in protein handling in endoplasmic reticulum (ER) and the following ER stress have been implicated in a vast number of diseases, such as amyotrophic lateral sclerosis (ALS). During excessive ER stress unfolded protein response (UPR) is activated to return ER to its normal physiological balance. The exact mechanisms of protein misfolding, accumulation and the following ER stress, which could lead to neurodegeneration, and the question whether UPR is a beneficial compensatory mechanism slowing down the neurodegenerative processes, are of interest. Protein disulphide isomerase (PDI) is a disulphide bond-modulating ER chaperone, which can also facilitate the ER-associated degradation (ERAD) of misfolded proteins. In this review we discuss the recent findings of ER stress, UPR and especially the role of PDI in ALS

Animal Models of Alzheimer’s Disease: Utilization of Transgenic Alzheimer’s Disease Models in Studies of Amyloid Beta Clearance

Glial cells in Alzheimer’s disease (AD) have been shown to be capable of clearing or at least restricting the accumulation of toxic amyloid beta (Aβ) deposits. Recently, bone marrow (BM)–derived monocytic cells have been recognized in experimental studies to be superior in their phagocytic properties when compared to their brain endogenous counterparts. In human AD, BM-derived monocytic cells may have deficiencies in their capacity to restrict plaque growth. Therefore, enhancement of phagocytic properties of cells of monocyte origin, both brain endogenous microglia and BM-derived monocytic cells, offers an attractive therapeutic approach to fight off AD. Transgenic mouse models with aberrant Aβ deposition offer a valuable tool for discovery of novel pathways to facilitate cell-mediated Aβ uptake. This article reviews the most recent findings on the phagocytic capacity of cells with monocytic origin in various transgenic AD models and describes the methods to study phagocytic activity of these cells

Utilization of APPswe/PS1dE9 Transgenic Mice in Research of Alzheimer's Disease: Focus on Gene Therapy and Cell-Based Therapy Applications

One of the most extensively used transgenic mouse model of Alzheimer's disease (AD) is APPswe/PS1dE9 mice, which over express the Swedish mutation of APP together with PS1 deleted in exon 9. These mice show increase in parenchymal Aβ load with Aβ plaques starting from the age of four months, glial activation, and deficits in cognitive functions at the age of 6 months demonstrated by radial arm water maze and 12-13 months seen with Morris Water Maze test. As gene transfer technology allows the delivery of DNA into target cells to achieve the expression of a protective or therapeutic protein, and stem cell transplantation may create an environment supporting neuronal functions and clearing Aβ plaques, these therapeutic approaches alone or in combination represent potential therapeutic strategies that need to be tested in relevant animal models before testing in clinics. Here we review the current utilization of APPswe/PS1dE9 mice in testing gene transfer and cell transplantation aimed at improving the protection of the neurons against Aβ toxicity and also reducing the brain levels of Aβ. Both gene therapy and cell based therapy may be feasible therapeutic approaches for human AD

Nontargeted Metabolite Profiling of Induced Pluripotent Stem Cells (iPSCs) Derived Neural Cells: Insights Into Mechanisms of Brain Diseases

Since the discovery that introduction of four specific genes encoding transcription factors convert mature human somatic cells into induced pluripotent stem cells (iPSCs), there has been an enormous increase in the applications of iPSC technologies to medical sciences, especially in modeling human diseases. In this review, we summarize recent advances in applying human iPSC reprogramming to generate patient-specific neural subtypes in order to reveal molecular pathways affected in various neurodegenerative diseases. Metabolites provide a functional readout of various cellular states enabling identification of biomarker candidates for early diagnosis, segregation of patient cohorts, and to follow-up disease progression or disease responses to novel therapies. With emerging technologies, that is, mass spectrometry and nuclear magnetic resonance applications to metabolomics and various software solutions of bioinformatics, it has become possible to measure thousands of metabolites simultaneously. These fascinating new techniques provide a powerful tool for setting scientific hypotheses and linking cellular pathways to biological mechanism. This review focuses on mass spectrometry-based metabolomics as a tool for iPSC research

The iPSC perspective on schizophrenia

Over a decade of schizophrenia research using human induced pluripotent stem cell (iPSC)-derived neural models has provided substantial data describing neurobiological characteristics of the disorder in vitro. Simultaneously, translation of the results into general mechanistic concepts underlying schizophrenia pathophysiology has been trailing behind. Given that modeling brain function using cell cultures is challenging, the gap between the in vitro models and schizophrenia as a clinical disorder has remained wide. In this review, we highlight reproducible findings and emerging trends in recent schizophrenia-related iPSC studies. We illuminate the relevance of the results in the context of human brain development, with a focus on processes coinciding with critical developmental periods for schizophrenia.Peer reviewe

Targeting Glycogen Synthase Kinase-3β for Therapeutic Benefit against Oxidative Stress in Alzheimer's Disease: Involvement of the Nrf2-ARE Pathway

Specific regions of the Alzheimer's disease (AD) brain are burdened with extracellular protein deposits, the accumulation of which is concomitant with a complex cascade of overlapping events. Many of these pathological processes produce oxidative stress. Under normal conditions, oxidative stress leads to the activation of defensive gene expression that promotes cell survival. At the forefront of defence is the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates a broad spectrum of protective genes. Glycogen synthase kinase-3β (GSK-3β) regulates Nrf2, thus making this kinase a potential target for therapeutic intervention aiming to boost the protective activation of Nrf2. This paper aims to review the neuroprotective role of Nrf2 in AD, with special emphasis on the role of GSK-3β in the regulation of the Nrf2 pathway. We also examine the potential of inducing GSK-3β by small-molecule activators, dithiocarbamates, which potentially exert their beneficial therapeutic effects via the activation of the Nrf2 pathway

Dysfunction of Cellular Proteostasis in Parkinson’s Disease

Despite decades of research, current therapeutic interventions for Parkinson’s disease (PD) are insufficient as they fail to modify disease progression by ameliorating the underlying pathology. Cellular proteostasis (protein homeostasis) is an essential factor in maintaining a persistent environment for neuronal activity. Proteostasis is ensured by mechanisms including regulation of protein translation, chaperone-assisted protein folding and protein degradation pathways. It is generally accepted that deficits in proteostasis are linked to various neurodegenerative diseases including PD. While the proteasome fails to degrade large protein aggregates, particularly alpha-synuclein (α-SYN) in PD, drug-induced activation of autophagy can efficiently remove aggregates and prevent degeneration of dopaminergic (DA) neurons. Therefore, maintenance of these mechanisms is essential to preserve all cellular functions relying on a correctly folded proteome. The correlations between endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) that aims to restore proteostasis within the secretory pathway are well-established. However, while mild insults increase the activity of chaperones, prolonged cell stress, or insufficient adaptive response causes cell death. Modulating the activity of molecular chaperones, such as protein disulfide isomerase which assists refolding and contributes to the removal of unfolded proteins, and their associated pathways may offer a new approach for disease-modifying treatment. Here, we summarize some of the key concepts and emerging ideas on the relation of protein aggregation and imbalanced proteostasis with an emphasis on PD as our area of main expertise. Furthermore, we discuss recent insights into the strategies for reducing the toxic effects of protein unfolding in PD by targeting the ER UPR pathway

Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases

Protein homeostasis (proteostasis) disturbances and inflammation are evident in normal aging and some age-related neurodegenerative diseases. While the proteostasis network maintains the integrity of intracellular and extracellular functional proteins, inflammation is a biological response to harmful stimuli. Cellular stress conditions can cause protein damage, thus exacerbating protein misfolding and leading to an eventual overload of the degradation system. The regulation of proteostasis network is particularly important in postmitotic neurons due to their limited regenerative capacity. Therefore, maintaining balanced protein synthesis, handling unfolding, refolding, and degrading misfolded proteins are essential to preserve all cellular functions in the central nervous sysytem. Failing proteostasis may trigger inflammatory responses in glial cells, and the consequent release of inflammatory mediators may lead to disturbances in proteostasis. Here, we review the mechanisms of proteostasis and inflammatory response, emphasizing their role in the pathological hallmarks of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, we discuss the interplay between proteostatic stress and excessive immune response that activates inflammation and leads to dysfunctional proteostasis

Neuronal Dynamics and miRNA Signaling Differ between SH-SY5Y APPSwe and PSEN1 Mutant iPSC-Derived AD Models upon Modulation with miR-124 Mimic and Inhibitor

Neuronal miRNA dysregulation may have a role in the pathophysiology of Alzheimer’s disease (AD). miRNA(miR)-124 is largely abundant and a critical player in many neuronal functions. However, the lack of models reliably recapitulating AD pathophysiology hampers our understanding of miR-124’s role in the disease. Using the classical human SH-SY5Y-APP695 Swedish neuroblastoma cells (SH-SWE) and the PSEN1 mutant iPSC-derived neurons (iNEU-PSEN), we observed a sustained upregulation of miR-124/miR-125b/miR-21, but only miR-124 was consistently shuttled into their exosomes. The miR-124 mimic reduced APP gene expression in both AD models. While miR-124 mimic in SH-SWE neurons led to neurite outgrowth, mitochondria activation and small Aβ oligomer reduction, in iNEU-PSEN cells it diminished Tau phosphorylation, whereas miR-124 inhibitor decreased dendritic spine density. In exosomes, cellular transfection with the mimic predominantly downregulated miR-125b/miR-21/miR-146a/miR-155. The miR-124 inhibitor upregulated miR-146a in the two experimental cell models, while it led to distinct miRNA signatures in cells and exosomes. In sum, though miR-124 function may be dependent on the neuronal AD model, data indicate that keeping miR-124 level strictly controlled is crucial for proper neuronal function. Moreover, the iNEU-PSEN cellular model stands out as a useful tool for AD mechanistic studies and perhaps for the development of personalized therapeutic strategies