Protein dyshomeostasis is the common mechanism of neurodegenerative diseases such as Alzheimer's disease (AD). Aging is the key risk factor, as the capacity of the proteostasis network declines ...during aging. Different cellular stress conditions result in the up-regulation of the neurotrophic, neuroprotective amyloid precursor protein (APP). Enzymatic processing of APP may result in formation of toxic Aβ aggregates (β-amyloids). Protein folding is the basis of life and death. Intracellular Aβ affects the function of subcellular organelles by disturbing the endoplasmic reticulum-mitochondria cross-talk and causing severe Ca
-dysregulation and lipid dyshomeostasis. The extensive and complex network of proteostasis declines during aging and is not able to maintain the balance between production and disposal of proteins. The effectivity of cellular pathways that safeguard cells against proteotoxic stress (molecular chaperones, aggresomes, the ubiquitin-proteasome system, autophagy) declines with age. Chronic cerebral hypoperfusion causes dysfunction of the blood-brain barrier (BBB), and thus the Aβ-clearance from brain-to-blood decreases. Microglia-mediated clearance of Aβ also declines, Aβ accumulates in the brain and causes neuroinflammation. Recognition of the above mentioned complex pathogenesis pathway resulted in novel drug targets in AD research.
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Background: Widespread protein aggregation occurs in the living system under stress or
during aging, owing to disturbance of endoplasmic reticulum (ER) proteostasis. Many neurodegenerative
diseases ...may have a common mechanism: the failure of protein homeostasis. Perturbation of
ER results in unfolded protein response (UPR). Prolonged chronical UPR may activate apoptotic
pathways and cause cell death.
Methods: Research articles on Sigma-1 receptor were reviewed.
Results: ER is associated to mitochondria by the mitochondria-associated ER-membrane, MAM.
The sigma-1 receptor (Sig-1R), a well-known ER-chaperone localizes in the MAM. It serves for
Ca2+-signaling between the ER and mitochondria, involved in ion channel activities and especially
important during neuronal differentiation. Sig-1R acts as central modulator in inter-organelle signaling.
Sig-1R helps cell survival by attenuating ER-stress. According to sequence based predictions
Sig-1R is a 223 amino acid protein with two transmembrane (2TM) domains. The X-ray structure
of the Sig-1R 1 showed a membrane-bound trimeric assembly with one transmembrane
(1TM) region. Despite the in vitro determined assembly, the results of in vivo studies are rather
consistent with the 2TM structure. The receptor has unique and versatile pharmacological profile.
Dimethyl tryptamine (DMT) and neuroactive steroids are endogenous ligands that activate Sig-1R.
The receptor has a plethora of interacting client proteins. Sig-1R exists in oligomeric structures
(dimer-trimer-octamer-multimer) and this fact may explain interaction with diverse proteins.
Conclusion: Sig-1R agonists have been used in the treatment of different neurodegenerative diseases,
e.g. Alzheimer's and Parkinson's diseases (AD and PD) and amyotrophic lateral sclerosis.
Utilization of Sig-1R agents early in AD and similar other diseases has remained an overlooked
therapeutic opportunity.
Neurodegenerative diseases (NDDs) are characterized by progressive deterioration of the structure and function of cells and their networks in the nervous system. There are currently no drugs or other ...treatments that can stop the progression of NDDs. NDDs have many similarities and common pathways, e.g., formation of misfolded amyloid proteins, intra- and extracellular amyloid deposits, and chronic inflammation. Initially, the inflammation process has a cytoprotective function; however, an elevated and prolonged immune response has damaging effects and causes cell death. Neuroinflammation has been a target of drug development for treating and curing NDDs. Treatment of different NDDs with non-steroid anti-inflammatory drugs (NSAIDs) has failed or has given inconsistent results. The use of NSAIDs in diagnosed Alzheimer's disease is currently not recommended. Sigma-1 receptor (Sig-1R) is a novel target for NDD drug development. Sig-1R plays a key role in cellular stress signaling, and it regulates endoplasmic reticulum stress and unfolded protein response. Activation of Sig-1R provides neuroprotection in cell cultures and animal studies. Clinical trials demonstrated that several Sig-1R agonists (pridopidine, ANAVEX3-71, fluvoxamine, dextrometorphan) and their combinations have a neuroprotective effect and slow down the progression of distinct NDDs.
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Using publicly available data sets, we compared pH in the human brain and the cerebrospinal fluid (CSF) of postmortem control and Alzheimer's disease cases. We further investigated the effects of ...long-term acidosis in vivo in the APP-PS1 mouse model of Alzheimer's disease. We finally examined in vitro whether low pH exposure could modulate the release of proinflammatory cytokines and the uptake of amyloid beta by microglia. In the human brain, pH decreased with aging. Similarly, we observed a reduction of pH in the brain of C57BL/6 mice with age. In addition, independent database analyses revealed that postmortem brain and CSF pH is further reduced in Alzheimer's disease cases compared with controls. Moreover, in vivo experiments showed that low pH CSF infusion increased amyloid beta plaque load in APP-PS1 mice. We further observed that mild acidosis reduced the amyloid beta 42–induced release of tumor necrosis factor–alpha by microglia and their capacity to uptake this peptide. Brain acidosis is associated with aging and might affect pathophysiological processes such as amyloid beta aggregation or inflammation in Alzheimer's disease.
•Normal aging correlates with brain pH decrease in human and mouse.•Alzheimer's disease is associated with a decrease of brain and CSF pH.•Low extracellular pH increased in vivo Aβ plaque load in a mouse model of AD.•In microglia, mild acidosis reduced Aβ-induced proinflammatory response and uptake.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
During the past 15 years, several genetically altered mouse models of human Alzheimer's disease (AD) have been developed. These costly models have greatly facilitated the evaluation of novel ...therapeutic approaches. Injecting synthetic β-amyloid (Aβ) 1-42 species into different parts of the brain of non-transgenic rodents frequently provided unreliable results, owing to a lack of a genuine characterization of the administered Aβ aggregates. Previously, we have published a new rat AD-model in which protofibrillar-fibrillar Aβ1-42 was administered into rat entorhinal cortex (Sipos 2007). In order to develop a more reliable model, we have injected well-characterized toxic soluble Aβ1-42 species (oligomers, protofibrils and fibrils) intracerebroventricularly (icv) into rat brain. Studies of the distribution of fluorescent-labeled Aβ1-42 in the brain showed that soluble Aβ-species diffused into all parts of the rat brain. After seven days, the Aβ-treated animals showed a significant decrease of spatial memory in Morris water maze test and impairment of synaptic plasticity (LTP) measured in acute hippocampal slices. The results of histological studies (decreased number of viable neurons, increased tau levels and decreased number of dendritic spines) also supported that icv administration of well-characterized toxic soluble Aβ species into rat brain provides a reliable rat AD-model.
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Alzheimer's disease (AD) is characterized by severe cognitive impairment and memory loss. AD is classified both into the "protein conformational" and the "endoplasmic reticulum-mitochondria stress" ...disorders. AD is a very complex, multifactorial disease of heterogeneous genetic and environmental background. The amyloid hypothesis of AD cannot fully explain the various clinical forms of the disease. Protein folding and misfolding in the endoplasmic reticulum (ER), and accumulation of several misfolded proteins (β-amyloid, Tau, alpha-synuclein, etc.) in ER and mitochondria (MT) may play a key role in the development of AD. Functional degradation of the synapse and the synapse holding neurites represents the first step in the pathogenesis of neurodegeneration. MT and ER are tightly coupled both physically and functionally with a special lipid raft called mitochondria-associated ER-membrane (MAM). MAM is crucial for Ca(2+) signalling and metabolic regulation of the cell. In turn, the impairment of ER-MT interplay is a common mechanism of different neurodegenerative diseases. In this review, we discuss recent findings focusing on the protein conformational and metabolic dysfunction, and the role of MAM and ER-MT crosstalk in neurodegeneration.
Heat-shock protein B1 (HSPB1) is among the most well-known and versatile member of the evolutionarily conserved family of small heat-shock proteins. It has been implicated to serve a neuroprotective ...role against various neurological disorders via its modulatory activity on inflammation, yet its exact role in neuroinflammation is poorly understood. In order to shed light on the exact mechanism of inflammation modulation by HSPB1, we investigated the effect of HSPB1 on neuroinflammatory processes in an in vivo and in vitro model of acute brain injury.
In this study, we used a transgenic mouse strain overexpressing the human HSPB1 protein. In the in vivo experiments, 7-day-old transgenic and wild-type mice were treated with ethanol. Apoptotic cells were detected using TUNEL assay. The mRNA and protein levels of cytokines and glial cell markers were examined using RT-PCR and immunohistochemistry in the brain. We also established primary neuronal, astrocyte, and microglial cultures which were subjected to cytokine and ethanol treatments. TNFα and hHSPB1 levels were measured from the supernates by ELISA, and intracellular hHSPB1 expression was analyzed using fluorescent immunohistochemistry.
Following ethanol treatment, the brains of hHSPB1-overexpressing mice showed a significantly higher mRNA level of pro-inflammatory cytokines (Tnf, Il1b), microglia (Cd68, Arg1), and astrocyte (Gfap) markers compared to wild-type brains. Microglial activation, and 1 week later, reactive astrogliosis was higher in certain brain areas of ethanol-treated transgenic mice compared to those of wild-types. Despite the remarkably high expression of pro-apoptotic Tnf, hHSPB1-overexpressing mice did not exhibit higher level of apoptosis. Our data suggest that intracellular hHSPB1, showing the highest level in primary astrocytes, was responsible for the inflammation-regulating effects. Microglia cells were the main source of TNFα in our model. Microglia isolated from hHSPB1-overexpressing mice showed a significantly higher release of TNFα compared to wild-type cells under inflammatory conditions.
Our work provides novel in vivo evidence that hHSPB1 overexpression has a regulating effect on acute neuroinflammation by intensifying the expression of pro-inflammatory cytokines and enhancing glial cell activation, but not increasing neuronal apoptosis. These results suggest that hHSPB1 may play a complex role in the modulation of the ethanol-induced neuroinflammatory response.
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Our goal was to explore the possible interactions of the potential metallodrug (η5-Cp*)Rh(III) complexes with histidine containing biomolecules (peptides/proteins) in order to understand the most ...important thermodynamic factors influencing the biospeciation and biotransformation of (η5-Cp*)Rh(III) complexes. To this end, here we report systematic solution thermodynamic and solution structural study on the interaction of (η5-Cp*)Rh(III) cation with histidine containing peptides and their constituents ((N-methyl)imidazole, GGA-OH, GGH-OH, histidine-amide, HGG-OH, GHG-NH2), based on extensive 1H NMR, ESI-MS and potentiometric investigations. The comparative evaluation of our data indicated that (η5-Cp*)Rh(III) cation is able to induce the deprotonation of amide nitrogen well below pH 7. Consequently, at physiological pH the peptides are coordinated to Rh(III) by tridentate manner, with the participation of amide nitrogen. At pH 7.4 the (η5-Cp*)Rh(III) binding affinity of peptides follow the order GGA-OH < < GGH-OH < < histidine-amide < HGG-OH < GHG-NH2, i.e. the observed binding strength essentially depends on the presence and position of histidine within the peptide sequence. We also performed computational study on the possible solution structures of complexes present at near physiological pH. At pH 7.4 all histidine containing peptides form ternary complexes with strongly coordinating (N,N) bidentate ligands (ethylenediamine or bipyridyl), in which the peptides are monodentately coordinated to Rh(III) through their imidazole N1‑nitrogens. In addition, the strongest chelators histidine-amide, HGG-OH and GHG-NH2 are also able to displace these powerful bidentate ligands from the coordination sphere of Rh(III).
The observed overall (η5-Cp*)Rh(III) binding strength and the Rh(III) affinity for amide nitrogen essentially depends on the presence and position of histidine within the peptide sequence. (η5-Cp*)Rh(III) complexes of strongly coordinating (N,N) bidentate ligands form ternary species with histidine containing peptides through the coordination of imidazole N1‑nitrogens. Display omitted
•(η5-Cp*)Rh(III) complexes of histidine containing peptides have been studied.•The binding strength depends on the presence and position of histidine unit.•(η5-Cp*)Rh(III) cation can induce the deprotonation of amide nitrogen well below pH 7.•In ternary complexes the peptides are bound to Rh(III) by their imidazole-N1 nitrogen.•Histidine peptides are also able to displace (N,N) bidentate ligands from Rh(III).
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Heterochiral homo-oligomers with alternating backbone configurations were constructed by using the different enantiomers of the cis- and trans-2-aminocyclopentanecarboxylic acid (ACPC) monomers. ...Molecular modeling and the spectroscopic techniques (NMR, ECD, and VCD) unequivocally proved that the alternating heterochiral cis-ACPC sequences form an H10/12 helix, where extra stabilization can be achieved via the cyclic side chains. The ECD and TEM measurements, together with molecular modeling, revealed that the alternating heterochiral trans-ACPC oligomers tend to attain a polar-strand secondary structure in solution, which can self-assemble into nanostructured fibrils. The observations indicate that coverage of all the possible secondary structures (various helix types and strand-mimicking conformations) can be attained with the help of cyclic β-amino acid diastereomers. A relationship has been established between the backbone chirality pattern and the prevailing secondary structure, which underlines the role of stereochemical control in the β-peptide secondary structure design and may contribute to future biological applications.
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