Toxic Protein Aggregates Research Articles

Protective Effects of Ambroxol on Aβ and α-Synuclein-Induced Neurotoxicity Through Glucocerebrosidase Activation in HT-22 Hippocampal Neuronal Cells.

Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disorder marked by the accumulation of α-synuclein (αSyn), often co-existing with amyloid β (Aβ) pathology. Current treatments are largely symptomatic, highlighting a critical need for disease-modifying therapies. Evidence suggests that αSyn aggregates contribute to neuronal death in DLB, particularly when exacerbated by Aβ. Given the role of autophagy in clearing misfolded proteins, exploring agents that promote this pathway is essential for developing effective treatments. Ambroxol (AMBX), a mucolytic drug, has demonstrated potential in activating glucocerebrosidase (GCase), an enzyme that enhances lysosomal function and facilitates the autophagic clearance of toxic protein aggregates, including αSyn. This study aims to evaluate AMBX's neuroprotective effects in a cellular model of DLB, with the goal of identifying new therapeutic agents that target the underlying pathology of DLB. In this study, HT-22 hippocampal neuronal cells were exposed to αSyn and Aβ, followed by AMBX treatment. Our results showed that AMBX significantly improved cell viability and reduced apoptosis in cells co-treated with αSyn and Aβ. Additionally, AMBX restored GCase activity, promoted autophagy, and reduced oxidative stress, which in turn mitigated αSyn aggregation and phosphorylation. These findings suggest that by activating GCase and enhancing autophagy, AMBX may help alleviate DLB-associated neurodegeneration. This study underscores the potential of AMBX as a therapeutic agent for DLB and supports further investigation in animal models and clinical trials to validate its efficacy in neurodegenerative disease contexts.

Amyloid beta-induced signalling in leptomeningeal cells and its impact on astrocyte response.

The pathological signature of Alzheimer's disease (AD) includes the accumulation of toxic protein aggregates, mainly consisting of amyloid beta (Aβ). Recent strides in fundamental research underscore the pivotal role of waste clearance mechanisms in the brain suggesting it may be an early indication of early onset AD. This study delves into the involvement of leptomeningeal cells (LMCs), crucial components forming integral barriers within the clearance system, in the context of AD. We examined the inflammatory cytokine responses of LMCs in the presence of Aβ, alongside assessments of LMC growth response, viability, oxidative stress, and changes in vimentin expression. The LMCs showed no changes in growth, viability, oxidative stress, or vimentin expression in the presence of Aβ, indicating that LMCs are less susceptible to Aβ damage compared to other CNS cells. However, LMCs exhibited a unique pro-inflammatory response to Aβ when compared to an LPS inflammatory control, showing an mRNA expression of pro-inflammatory cytokines such IL-6, IL-10 and IL-33 but no changes in IL-1α and IL-1β. Furthermore, LMCs influenced the astrocyte response to Aβ, as conditioned media from Aβ-treated LMCs was observed to downregulate somatic S100β in astrocytes. We also investigated whether the JAK/STAT3 pathway was involved in the Aβ response of the LMCs, as this pathway has been shown to be activated in astrocytes and neurons in the presence of Aβ. JAK/STAT3 activation was assessed through phosphorylated STAT3, revealing that JAK/STAT3 was not active in the cells when in the presence of Aβ. However, when JAK1 and JAK2 were inhibited, cytokine protein levels of IL7, IL10, IL15 and IL33 levels, which had shown alteration when LMCs were treated with Aβ, returned to base levels. This indicates that although JAK1/STAT3 and JAK2/STAT3 are not the direct pathway for Aβ response in LMCs, JAK1 and JAK2 may still play a role in regulating cytokine levels, potentially through indirect means or crosstalk. Overall, our findings reveal that LMCs are resilient to Aβ toxicity and suggest that JAK1/STAT3 and JAK2/STAT3 does not play a central role in the inflammatory response, providing new insights into the cellular mechanisms underlying AD.

Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis.

Antisense oligonucleotides, which are used to silence target genes, are gaining attention as a novel drug discovery modality for proteinopathies. However, while clinical trials for neurodegenerative diseases like amyotrophic lateral sclerosis have been conducted in recent years, the results have not always been favorable. The results from a Phase III trial of the antisense oligonucleotide, that is, tofersen, which targets SOD1 mRNA, showed decreased levels of cerebrospinal fluid SOD1 and plasma neurofilament light chain but no improvements in primary clinical endpoint. Moreover, case reports pertaining to patients with amyotrophic lateral sclerosis carrying FUS and C9orf72 mutations who received antisense oligonucleotide-based treatments have demonstrated a notable reduction in the targeted protein (thus providing the proof of mechanism) but with no discernible clinical benefits. There are several possible reasons why antisense oligonucleotides knockdown fails to achieve proof of concept, which need to be addressed: on-target adverse effects resulting from the loss of function of target gene and irreversible neuronal death cascade due to toxic protein accumulation, among other factors. This review provides an overview of the current status and discusses the prospects of antisense oligonucleotides treatment for amyotrophic lateral sclerosis.

Conformational Selection of α-Synuclein Tetramers at Biological Interfaces.

Controlling the polymorphic assemblies of α-synuclein (αS) oligomers is crucial to reroute toxic protein aggregation implicated in Parkinson's disease (PD). One potential mediator is the interaction of αS tetramers with cell membranes, which may regulate the dynamic balance between aggregation-prone disordered monomers and aggregation-resistant helical tetramers. Here, we model diverse tetramer-cell interactions and compare the structure-function relations at the supramolecular-biological interface with available experimental data. The models predict preferential interaction of compact αS tetramers with highly charged membrane surfaces, which may further stabilize this aggregation-resistant conformer. On moderately charged membranes, extended structures are preferred. In addition to surface charge, curvature influences tetramer thermodynamic stability and aggregation, with potential for selective isolation of tetramers via regio-specific interactions with strongly negatively charged micelles that screen further aggregation. Our modeling data set highlights diverse beneficial nano-bio interactions to redirect biomolecule assembly, supporting new therapeutic approaches for PD based on lipid-mediated conformational selection and inhibition.

Therapies Using Anti-Diabetics to Prevent and Manage Progression of Parkinson's Disease

<p>Currently, a significant proportion of older individuals have demonstrated connections between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM). Emerging evidence from cohort studies, clinical data, and preclinical meta-analyses reveals that T2DM patients have an increased risk of developing PD, often accompanied by more severe disease progression. These two chronic conditions are believed to share common pathways. The pathways that likely connect the neurodegenerative process of PD include autophagy, mitochondrial dysfunction, dysregulated insulin signaling, inflammation, and insulin resistance. Preclinical PD models highlight the importance of cerebral insulin signaling, which confers numerous neuroprotective benefits. Several ongoing phase II and phase III trials are being conducted in PD-affected populations. These trials reflect the potential of existing anti-diabetic medications to improve PD motor symptoms and halt the progression of neurodegeneration. Brain insulin resistance plays a crucial role in the pathophysiology of PD. The insulin signaling pathway represents a promising novel target for disease modification in both diabetic and non-diabetic PD. Incretin receptors in the brain have emerged as the most promising targets for repurposing existing drugs in PD treatment. Targeting these receptors mitigates inflammation, apoptosis, toxic protein aggregation, long-term potentiation, autophagy, and insulin signaling failure. </p><p> Presently, various novel anti-diabetic targets are available that can regulate the insulin signaling pathway in dopaminergic neurons, suggesting improvements in cognitive function and significant neuroprotective effects in PD. Throughout neurodegenerative processes, insulin and incretins exert therapeutic effects in multiple manners. Preclinical studies have demonstrated that glucagon-- like peptide 1 (GLP-1) receptor agonists reduce neuroinflammation, tau phosphorylation, and amyloid deposition while increasing synaptic function and enhancing memory formation. Incretin mimetics may act through the restoration of insulin signaling pathways, inducing further neuroprotective effects. </p><p> This review examined the reported shared cellular and molecular pathologies between PD and T2DM, and explored the repurposing of anti-diabetic drugs for the prevention of PD progression through the regulation of insulin signaling pathways.</p>

Multifunctional Copper-Phenolic Nanopills Achieve Comprehensive Polyamines Depletion to Provoke Enhanced Pyroptosis and Cuproptosis for Cancer Immunotherapy.

The overexpression of polyamines in tumor cells contributes to the establishment of immunosuppressive microenvironment and facilitates tumor growth. Here, it have ingeniously designed multifunctional copper-piceatannol/HA nanopills (Cu-Pic/HA NPs) that effectively cause total intracellular polyamines depletion by inhibiting polyamines synthesis, depleting intracellular polyamines, and impairing polyamines uptake, resulting in enhanced pyroptosis and cuproptosis, thus activating a powerful immune response to achieve anti-tumor therapy. Mitochondrial dysfunction resulting from overall intracellular polyamines depletion not only leads to the surge of copper ions in mitochondria, thereby causing the aggregation of toxic proteins to induce cuproptosis, but also triggers the accumulation of reactive oxygen species (ROS) within mitochondria, which further upregulates the expression of zDHHC5 and zDHHC9 to promote the palmitoylation of gasdermin D (GSDMD) and GSDMD-N, ultimately inducing enhanced pyroptosis. Then the occurrence of enhanced pyroptosis and cuproptosis is conductive to remodel the immunosuppressive tumor microenvironment, thus activating anti-tumor immune responses and ultimately effectively inhibiting tumor growth and metastasis. This therapeutic strategy of enhanced pyroptosis and cuproptosis through comprehensive polyamines depletion provides a novel template for cancer immunotherapy.

A singular plasmonic-thermoelectric hollow nanostructure inducing apoptosis and cuproptosis for catalytic cancer therapy

Thermoelectric technology has recently emerged as a distinct therapeutic modality. However, its therapeutic effectiveness is significantly limited by the restricted temperature gradient within living organisms. In this study, we introduce a high-performance plasmonic-thermoelectric catalytic therapy utilizing urchin-like Cu2−xSe hollow nanospheres (HNSs) with a cascade of plasmonic photothermal and thermoelectric conversion processes. Under irradiation by a 1064 nm laser, the plasmonic absorption of Cu2−xSe HNSs, featuring rich copper vacancies (VCu), leads to a rapid localized temperature gradient due to their exceptionally high photothermal conversion efficiency (67.0%). This temperature gradient activates thermoelectric catalysis, generating toxic reactive oxygen species (ROS) targeted at cancer cells. Density functional theory calculations reveal that this vacancy-enhanced thermoelectric catalytic effect arises from a much more carrier concentration and higher electrical conductivity. Furthermore, the exceptional photothermal performance of Cu2−xSe HNSs enhances their peroxidase-like and catalase-like activities, resulting in increased ROS production and apoptosis induction in cancer cells. Here we show that the accumulation of copper ions within cancer cells triggers cuproptosis through toxic mitochondrial protein aggregation, creating a synergistic therapeutic effect. Tumor-bearing female BALB/c mice are used to evaluate the high anti-cancer efficiency. This innovative approach represents the promising instance of plasmonic-thermoelectric catalytic therapy, employing dual pathways (membrane potential reduction and thioctylated protein aggregation) of mitochondrial dysfunction, all achieved within a singular nanostructure. These findings hold significant promise for inspiring the development of energy-converting nanomedicines.

Long Noncoding RNA NR_030777 Alleviates Cobalt Nanoparticles-Induced Neurodegenerative Damage by Promoting Autophagosome-Lysosome Fusion.

Potential exposure to cobalt nanoparticles (CoNPs) occurs in various fields, including hard alloy industrial production, the increasing use of new energy lithium-ion batteries, and millions of patients with metal-on-metal joint prostheses. Evidence from human, animal, and in vitro experiments suggests a close relationship between CoNPs and neurotoxicity. However, a systematic assessment of central nervous system (CNS) impairment due to CoNPs exposure and the underlying molecular mechanisms is lacking. In this study, we found that CoNPs induced neurodegenerative damage both in vivo and in vitro, including cognitive impairment, β-amyloid deposition and Tau hyperphosphorylation. CoNPs promoted the formation of autophagosomes and impeding autophagosomal-lysosomal fusion in vivo and in vitro, leading to toxic protein accumulation. Moreover, CoNPs exposure reduced the level of transcription factor EB (TFEB) and the abundance of lysosome, causing a blockage in autophagosomal-lysosomal fusion. Interestingly, overexpression of long noncoding RNA NR_030777 mitigated CoNPs-induced neurodegenerative damage in both in vivo and in vitro models. Fluorescence in situ hybridization assay revealed that NR_030777 directly binds and stabilizes TFEB mRNA, alleviating the blockage of autophagosomal-lysosomal fusion and ultimately restoring neurodegeneration induced by CoNPs in vivo and in vitro. In summary, our study demonstrates that autophagic dysfunction is the main toxic mechanism of neurodegeneration upon CoNPs exposure and NR_030777 plays a crucial role in CoNPs-induced autophagic dysfunction. Additionally, the proposed adverse outcome pathway contributes to a better understanding of CNS toxicity assessment of CoNPs.

Repetitive Head Impacts and Perivascular Space Volume in Former American Football Players

Exposure to repetitive head impacts (RHI) is associated with increased risk for neurodegeneration. Accumulation of toxic proteins due to impaired brain clearance is suspected to play a role. To investigate whether perivascular space (PVS) volume is associated with lifetime exposure to RHI in individuals at risk for RHI-associated neurodegeneration. This cross-sectional study was part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project, a 7-year multicenter study consisting of 4 US study sites. Data were collected from September 2016 to February 2020 and analyses were performed between May 2021 and October 2023. After controlling for magnetic resonance image (MRI) and processing quality, former American football players and unexposed asymptomatic control participants were included in analyses. Prior exposure to RHI while participating in American football was estimated using the 3 cumulative head impact indices (CHII-G, linear acceleration; CHII-R, rotational acceleration; and CHII, number of head impacts). Individual PVS volume was calculated in the white matter of structural MRI. Cognitive impairment was based on neuropsychological assessment. Linear regression models were used to assess associations of PVS volume with neuropsychological assessments in former American football players. All analyses were adjusted for confounders associated with PVS volume. Analyses included 224 participants (median [IQR] age, 57 [51-65] years), with 170 male former football players (114 former professional athletes, 56 former collegiate athletes) and 54 male unexposed control participants. Former football players had larger PVS volume compared with the unexposed group (mean difference, 0.28 [95% CI, 0.00-0.56]; P = .05). Within the football group, PVS volume was associated with higher CHII-R (β = 2.71 × 10-8 [95% CI, 0.50 × 10-8 to 4.93 × 10-8]; P = .03) and CHII-G (β = 2.24 × 10-6 [95% CI, 0.35 × 10-6 to 4.13 × 10-6]; P = .03). Larger PVS volume was also associated with worse performance on cognitive functioning in former American football players (β = -0.74 [95% CI, -1.35 to -0.13]; P = .04). These findings suggest that impaired perivascular brain clearance, as indicated by larger PVS volume, may contribute to the association observed between RHI exposure and neurodegeneration.

Increased SNAI2 expression and defective collagen adhesion in cells with pediatric dementia, juvenile ceroid lipofuscinosis

Dementia-related neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), are known to be caused by accumulation of toxic proteins. However, the molecular mechanisms that cause neurodegeneration and its biophysical effects on cells remain unclear. In this study, we used juvenile neuronal ceroid lipofuscinosis (JNCL), a pediatric dementia with a clear etiology of mutations in ceroid lipofuscinosis neuronal 3 (CLN3), to explore the changes in cell adhesion, a biophysical process that regulates neuronal development and survival. We used JNCL cerebral organoid gene expression datasets to identify the biological pathways that affect neural development, and found enriched gene expression in the epithelial-mesenchymal transition (EMT) pathway and increased expression of its inducer snail family transcriptional repressor 2 (SNAI2). A cell adhesion assay using lymphoblasts from patients with JNCL revealed defective adhesion to cell culture plates, glass surfaces, collagen type I, and neuroblast-like cells. To determine whether inhibition of EMT could improve the cell adhesion of JNCL lymphoblasts, we used all-trans retinoic acid, a well-known EMT inhibitor and inducer of neural differentiation. In JNCL lymphoblasts, ATRA treatment enhanced adhesion to collagen type I and these effects were abolished by Ca2+ chelator. These results provide new insights into the role of CLN3 and cell adhesion in the pathogenesis of NDD.

Polyphenols alleviate metabolic disorders: the role of ubiquitin-proteasome system.

Metabolic disorders include obesity, nonalcoholic fatty liver disease, insulin resistance and type 2 diabetes. It has become a major health issue around the world. Ubiquitin-proteasome system (UPS) is essential for nearly all cellular processes, functions as a primary pathway for intracellular protein degradation. Recent researches indicated that dysfunctions in the UPS may result in the accumulation of toxic proteins, lipotoxicity, oxidative stress, inflammation, and insulin resistance, all of which contribute to the development and progression of metabolic disorders. An increasing body of evidence indicates that specific dietary polyphenols ameliorate metabolic disorders by preventing lipid synthesis and transport, excessive inflammation, hyperglycemia and insulin resistance, and oxidative stress, through regulation of the UPS. This review summarized the latest research progress of natural polyphenols improving metabolic disorders by regulating lipid accumulation, inflammation, oxidative stress, and insulin resistance through the UPS. In addition, the possible mechanisms of UPS-mediated prevention of metabolic disorders are comprehensively proposed. We aim to provide new angle to the development and utilization of polyphenols in improving metabolic disorders.

Abstract Tu066: Loss of Sigmar1 Aggravated Cardiac Proteotoxicity and Cardiac Dysfunction in Mutant αB-Crystallin Mouse

Background: Deposition of misfolded protein aggregates observed in diverse cardiac disease models leads to proteotoxic cardiomyopathy. In earlier studies, we confirmed mutations in α-B-Crystallin, specifically Arg120Gly (CryAB R120G ), develop proteotoxic cardiomyopathy. Cardiomyocyte-specific CryAB R120G overexpression leads to cardiac dysfunction resulting from the accumulation of toxic pre-amyloid oligomers and protein aggregation. In the event of proteotoxic insult, the chaperone proteins function to prevent the accumulation of protein aggregates. One of the multitasking chaperone proteins in the heart is Sigmar1, whose role in proteotoxic cardiomyopathy and protein aggregation remains unknown. Hypothesis: We hypothesize that Sigmar1 plays an essential role in protein aggregate clearance, and the absence of Sigmar1 in CryAB R120G mice aggravates pathological cardiac remodeling. Methods and Result: We measured Sigmar1 expression level in CryAB R120G hearts and found a significant reduction in endogenous Sigmar1 protein and transcript levels in CryAB R120G hearts. Co-immunoprecipitation and yeast-two-hybrid assays demonstrated a direct interaction between Sigmar1 and CryAB. Therefore, we evaluated Sigmar1’s function in the proteotoxic model of heart failure. We ablated Sigmar1 in CryAB R120G , expressing myocytes both in vitro by using Sigmar1 siRNA and in vivo by crossing Sigmar1 knockout with CryAB R120G (CryAB R120G xSigmar1 -/- ) . Both i n vitro and in vivo studies displayed a dramatic increase in protein aggregate size and content in CryAB R120G xSigmar1 -/- heart, assessed by immunostaining and electron microscopy. Echocardiography showed age-dependent aggravation of cardiac contractile dysfunction, and Masson’s Trichrome staining showed increased cardiac fibrosis in the CryAB R120G xSigmar1 -/- hearts compared to CryAB R120G hearts. Conclusion: Overall, we found that Sigmar1 directly interacts with CryAB and plays a vital role in the degradation of protein aggregates where the absence of Sigmar1 causes increased protein aggregate size and content in CryAB R120G mice, leading to aggravated pathology with ventricular dysfunction, increased interstitial fibrosis, and cardiac hypertrophy.

Spatial selectivity of ATase inhibition in mouse models of Charcot-Marie-Tooth disease.

The endoplasmic reticulum acetylation machinery has emerged as a new branch of the larger endoplasmic reticulum quality control system. It regulates the selection of correctly folded polypeptides as well as reticulophagy-mediated removal of toxic protein aggregates with the former being a particularly important aspect of the proteostatic functions of endoplasmic reticulum acetylation. Essential to this function is the Nε-lysine acetyltransferase activity of acetyltransferase 1 and acetyltransferase 2, which regulates the induction of endoplasmic reticulum-specific autophagy through the acetylation of the autophagy-related protein 9A. Here, we used three mouse models of Charcot-Marie-Tooth disease, peripheral myelin protein 22/Tr-J, C3-peripheral myelin protein 22 and myelin protein zero/ttrr, to study spatial and translational selectivity of endoplasmic reticulum acetyltransferase inhibitors. The results show that inhibition of the endoplasmic reticulum acetyltransferases selectively targets misfolding/pro-aggregating events occurring in the lumen of the organelle. Therefore, they establish acetyltransferase 1 and acetyltransferase 2 as the first proven targets for disease-causing proteotoxic states that initiate within the lumen of the endoplasmic reticulum/secretory pathway.

Walnut oil: a promising nutraceutical in reducing oxidative stress and improving cholinergic activity in an in vitro Alzheimer's disease model.

Improving the quality of life in elderly patients and finding new treatment options for neurological diseases such as Alzheimer's has become one of the priorities in the scientific world. In recent years, the beneficial effects and therapeutic properties of natural foods on neurological health have become a very remarkable issue. Walnut oil (WO) is a promising nutraceutical, with many phytochemicals and polyunsaturated fatty acids and is thought to be promising in the treatment of many neurological diseases and cognitive deficits, such as Alzheimer's disease (AD). Polyphenolic compounds found in WO enhance intraneuronal signaling and neurogenesis and improve the sequestration of insoluble toxic protein aggregates. The objective of this study was to investigate the potential protective and therapeutic effects of WO in a model of AD induced by retinoic acid (RA) and brain-derived neurotrophic factor (BDNF). In order to achieve this, the experimental groups were formed as follows: Control group, WO group, Alzheimer's disease (AD) group, AD+WO applied group (AD+WO). WO supplementation almost significantly reduced oxidative stress in the ad model, providing 2-fold protection against protein oxidation. Additionally, WO showed a significant reduction in tau protein levels (2-fold), increased acetylcholine (ACh) levels (12%), and decreased acetylcholine esterase (AChE) activity (~50%). Since it has been known for centuries that WO does show any adverse effects on human health and has neuroprotective properties, it may be used in the treatment of AD as an additional nutraceutical to drug treatments.

Natural Bioactive Compounds from Macroalgae and Microalgae for the Treatment of Alzheimer's Disease: A Review.

Neuroinflammation, toxic protein aggregation, oxidative stress, and mitochondrial dysfunction are key pathways in neurodegenerative diseases like Alzheimer's disease (AD). Targeting these mechanisms with antioxidants, anti-inflammatory compounds, and inhibitors of Aβ formation and aggregation is crucial for treatment. Marine algae are rich sources of bioactive compounds, including carbohydrates, phenolics, fatty acids, phycobiliproteins, carotenoids, fatty acids, and vitamins. In recent years, they have attracted interest from the pharmaceutical and nutraceutical industries due to their exceptional biological activities, which include anti-inflammation, antioxidant, anticancer, and anti-apoptosis properties. Multiple lines of evidence have unveiled the potential neuroprotective effects of these multifunctional algal compounds for application in treating and managing AD. This article will provide insight into the molecular mechanisms underlying the neuroprotective effects of bioactive compounds derived from algae based on in vitro and in vivo models of neuroinflammation and AD. We will also discuss their potential as disease-modifying and symptomatic treatment strategies for AD.

Rosmarinic acid ameliorated oxidative stress, neuronal injuries, and mitochondrial dysfunctions mediated by polyglutamine and ɑ-synuclein in Caenorhabditis elegans models.

Numerous natural antioxidants have been developed into agents for neurodegenerative diseases (NDs) treatment. Rosmarinic acid (RA), an excellent antioxidant, exhibits neuroprotective activity, but its anti-NDs efficacy remains puzzling. Here, Caenorhabditis elegans models were employed to systematically reveal RA-mediated mechanisms in delaying NDs from diverse facets, including oxidative stress, the homeostasis of neural and protein, and mitochondrial disorders. Firstly, RA significantly inhibited reactive oxygen species accumulation, reduced peroxide malonaldehyde production, and strengthened the antioxidant defense system via increasing superoxide dismutase activity. Besides, RA reduced neuronal loss and ameliorated polyglutamine and ɑ-synuclein-mediated dyskinesia in NDs models. Further, in combination with the data and molecular docking results, RA may bind specifically to Huntington protein and ɑ-synuclein to prevent toxic protein aggregation and thus enhance proteostasis. Finally, RA ameliorated mitochondrial dysfunction including increasing adenosine triphosphate and mitochondrial membrane potential levels and rescuing mitochondrial membrane proteins' expressions and mitochondrial structural abnormalities via regulating mitochondrial dynamics genes and improving the mitochondrial kinetic homeostasis. Thus, this study systematically revealed the RA-mediated neuroprotective mechanism and promoted RA as a promising nutritional intervention strategy to prevent NDs.

Exploiting sweet relief for preeclampsia by targeting autophagy-lysosomal machinery and proteinopathy

The etiology of preeclampsia (PE), a severe complication of pregnancy with several clinical manifestations and a high incidence of maternal and fetal morbidity and mortality, remains unclear. This issue is a major hurdle for effective treatment strategies. We recently demonstrated that PE exhibits an Alzheimer-like etiology of impaired autophagy and proteinopathy in the placenta. Targeting of these pathological pathways may be a novel therapeutic strategy for PE. Stimulation of autophagy with the natural disaccharide trehalose and its lacto analog lactotrehalose in hypoxia-exposed primary human trophoblasts restored autophagy, inhibited the accumulation of toxic protein aggregates, and restored the ultrastructural features of autophagosomes and autolysosomes. Importantly, trehalose and lactotrehalose inhibited the onset of PE-like features in a humanized mouse model by normalizing autophagy and inhibiting protein aggregation in the placenta. These disaccharides restored the autophagy-lysosomal biogenesis machinery by increasing nuclear translocation of the master transcriptional regulator TFEB. RNA-seq analysis of the placentas of mice with PE indicated the normalization of the PE-associated transcriptome profile in response to trehalose and lactotrehalose. In summary, our results provide a novel molecular rationale for impaired autophagy and proteinopathy in patients with PE and identify treatment with trehalose and its lacto analog as promising therapeutic options for this severe pregnancy complication.

Brain chains as topological signatures for Alzheimer’s disease

AbstractTopology is providing new insights for neuroscience. For instance, graphs, simplicial complexes, directed graphs, flag complexes, persistent homology and convex covers have been used to study functional brain networks, synaptic connectivity, and hippocampal place cell codes. We propose a topological framework to study the evolution of Alzheimer’s disease, the most common neurodegenerative disease. The modeling of this disease starts with the representation of the brain connectivity as a graph and the seeding of a toxic protein in a specific region represented by a vertex. Over time, the accumulation of toxic proteins at vertices and their propagation along edges are modeled by a dynamical system on this graph. These dynamics provide an order on the edges of the graph according to the damage created by high concentrations of proteins. This sequence of edges defines a filtration of the graph. We consider different filtrations given by different disease seeding locations. To study these filtrations we propose a new combinatorial and topological method. A filtration defines a maximal chain in the partially ordered set of spanning subgraphs ordered by inclusion. To identify similar graphs, and define a topological signature, we quotient this poset by graph homotopy equivalence, which gives maximal chains in a smaller poset. We provide an algorithm to compute this direct quotient without computing all subgraphs and then propose bounds on the total number of graphs up to homotopy equivalence. To compare the maximal chains generated by this method, we extend Kendall’s $$d_K$$ d K metric for permutations to more general graded posets and establish bounds for this metric. We then demonstrate the utility of this framework on actual brain graphs by studying the dynamics of tau proteins on the structural connectome. We show that the proposed topological brain chain equivalence classes distinguish different simulated subtypes of Alzheimer’s disease.

Deciphering the Enigma of Neuron-Glial Interactions in Neurological Disorders.

Innate lymphocytes, including microglial cells, astrocytes, and oligodendrocytes, play a crucial role in initiating neuroinflammatory reactions inside the central nervous system (CNS). The prime focus of this paper is on the involvement and interplay of neurons and glial cells in neurological disorders such as Alzheimer's Disease (AD), Autism Spectrum Disorder (ASD), epilepsy, and multiple sclerosis (MS). In this review, we explore the specific contributions of microglia and astrocytes and analyzes multiple pathways implicated in neuroinflammation and disturbances in excitatory and inhibitory processes. Firstly, we elucidate the mechanisms through which toxic protein accumulation in AD results in synaptic dysfunction and deregulation of the immune system and examines the roles of microglia, astrocytes, and hereditary factors in the pathogenesis of the disease. Secondly, we focus on ASD and the involvement of glial cells in the development of the nervous system and the formation of connections between neurons and investigates the genetic connections associated with these processes. Lastly, we also address the participation of glial cells in epilepsy and MS, providing insights into their pivotal functions in both conditions. We also tried to give an overview of seven different pathways like toll-like receptor signalling pathway, MyD88-dependent and independent pathway, etc and its relevance in the context with these neurological disorders. In this review, we also explore the role of activated glial cells in AD, ASD, epilepsy, and MS which lead to neuroinflammation. Even we focus on excitatory and inhibitory imbalance in all four neurological disorders as imbalance affect the proper functioning of neuronal circuits. Finally, this review concludes that there is necessity for additional investigation on glial cells and their involvement in neurological illnesses.

Role of TFEB in Huntington's Disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expansion of the CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. This expansion leads to a polyglutamine (polyQ) tract at the N-terminal end of HTT, which reduces the solubility of the protein and promotes its accumulation. Inefficient clearance of mutant HTT (mHTT) by the proteasome or autophagy-lysosomal system leads to accumulation of oligomers and toxic protein aggregates in neurons, resulting in impaired proteolytic systems, transcriptional dysregulation, impaired axonal transport, mitochondrial dysfunction and cellular energy imbalance. Growing evidence suggests that the accumulation of mHTT aggregates and autophagic and/or lysosomal dysfunction are the major pathogenic mechanisms underlying HD. In this context, enhancing autophagy may be an effective therapeutic strategy to remove protein aggregates and improve cell function. Transcription factor EB (TFEB), a master transcriptional regulator of autophagy, controls the expression of genes critical for autophagosome formation, lysosomal biogenesis, lysosomal function and autophagic flux. Consequently, the induction of TFEB activity to promote intracellular clearance may be a therapeutic strategy for HD. However, while some studies have shown that overexpression of TFEB facilitates the clearance of mHTT aggregates and ameliorates the disease phenotype, others indicate such overexpression may lead to mHTT co-aggregation and worsen disease progression. Further studies are necessary to confirm whether TFEB modulation could be an effective therapeutic strategy against mHTT-mediated toxicity in different disease models.