Abnormal Protein Aggregation Research Articles

Neuroprotective Effects of Myrtle Berry By-Product Extracts on 6-OHDA-Induced Cytotoxicity in PC12 Cells

The rising global focus on healthy lifestyles and environmental sustainability has prompted interest in repurposing plant-based by-products for health benefits. With increasing life expectancy, the incidence of neurodegenerative diseases—characterized by complex, multifactorial mechanisms such as abnormal protein aggregation, mitochondrial dysfunction, oxidative stress, and inflammation—continues to grow. Medicinal plants, with their diverse bioactive compounds, offer promising therapeutic avenues for such conditions. Myrtus communis L., a Mediterranean plant primarily used in liquor production, generates significant waste rich in antioxidant and anti-inflammatory properties. This study explores the neuroprotective potential of Myrtus berry by-products in a cellular model of neurodegeneration. Using PC12 cells exposed to 6-hydroxydopamine (6-OHDA), we assessed cell viability via MTT assay and measured reactive oxygen species (ROS) production using DCFDA fluorescence. Additionally, we analyzed the expression of genes linked to oxidative stress and neuronal function, including AChE, PON2, Grin1, Gabrd, and c-fos, by RT-PCR. Our findings reveal that Myrtus extract significantly protects against 6-OHDA-induced cytotoxicity, reduces ROS levels, and modulates the expression of key stress-related genes, underscoring its potential as a neuroprotective agent. These results highlight the therapeutic promise of Myrtus extracts in mitigating neurodegenerative processes, paving the way for future interventions.

Artificial enforcement of the unfolded protein response (UPR) reduces disease features in multiple preclinical models of ALS/FTD.

Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) are part of a spectrum of diseases that share several causative genes, resulting in a combinatory of motor and cognitive symptoms and abnormal protein aggregation. Multiple unbiased studies have revealed that proteostasis impairment at the level of the endoplasmic reticulum (ER) is a transversal pathogenic feature of ALS/FTD. The transcription factor XBP1s is a master regulator of the unfolded protein response (UPR), the main adaptive pathway to cope with ER stress. Here we provide evidence of suboptimal activation of the UPR in ALS/FTD models under experimental ER stress. To artificially engage the UPR, we intracerebroventricularly administrated adeno-associated viruses (AAV) to express the active form of XBP1 (XBP1s) in the nervous system of ALS/FTD models. XBP1s expression improved motor performance and extended life span of mutant SOD1 mice, associated with reduced protein aggregation. AAV-XBP1s administration also attenuated disease progression in models of TDP-43 and C9orf72 pathogenesis. Proteomic profiling of spinal cord tissue revealed that XBP1s overexpression improved proteostasis and modulated the expression of a cluster of synaptic and cell morphology proteins. Our results suggest that strategies to improve ER proteostasis may serve as a pan-therapeutic strategy to treat ALS/FTD.

The Crucial Role of the Blood–Brain Barrier in Neurodegenerative Diseases: Mechanisms of Disruption and Therapeutic Implications

The blood–brain barrier (BBB) is a crucial structure that maintains brain homeostasis by regulating the entry of molecules and cells from the bloodstream into the central nervous system (CNS). Neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, as well as ischemic stroke, compromise the integrity of the BBB. This leads to increased permeability and the infiltration of harmful substances, thereby accelerating neurodegeneration. In this review, we explore the mechanisms underlying BBB disruption, including oxidative stress, neuroinflammation, vascular dysfunction, and the loss of tight junction integrity, in patients with neurodegenerative diseases. We discuss how BBB breakdown contributes to neuroinflammation, neurotoxicity, and the abnormal accumulation of pathological proteins, all of which exacerbate neuronal damage and facilitate disease progression. Furthermore, we discuss potential therapeutic strategies aimed at preserving or restoring BBB function, such as anti-inflammatory treatments, antioxidant therapies, and approaches to enhance tight junction integrity. Given the central role of the BBB in neurodegeneration, maintaining its integrity represents a promising therapeutic approach to slow or prevent the progression of neurodegenerative diseases.

Deep learning-based denoising for unbiased analysis of morphology and stiffness in amyloid fibrils.

Understanding the morphology of amyloid fibrils is crucial for comprehending the aggregation and degradation mechanisms of abnormal proteins implicated in various diseases, such as Alzheimer's disease, Parkinson's disease, type II diabetes, and various forms of amyloidosis. Atomic force microscopy (AFM) stands as the most representative method for studying amyloid fibril morphology. However, obstacles in AFM images, including noise, salt, and amorphous aggregates, often impede accurate sample quantification. In this study, we developed denoising software employing a U-Net deep learning architecture to address this issue. The software efficiently eliminated various impediments that interfere with fibril analysis in noisy AFM images, thereby facilitating precise quantification of amyloid fibrils. We also developed automated fibril analysis technologies using the denoised AFM images, leading to quicker, more precise, and more objective assessments of fibril morphology. Furthermore, we presented a method for fibril stiffness extraction from a modulus image through mask creation based on a denoised height image. Our approach secures time efficiency and precision in analyzing amyloid morphology, and we believe it will significantly advance the currently stagnant research on amyloid-related diseases.

Multifunctional Hydroxyquinoline-Derived Turn-on Fluorescent Probe for Alzheimer's Disease Detection and Therapy

Understanding molecular motifs that can interfere with amyloid fibrillation through non-covalent interactions is essential for addressing abnormal protein aggregation and associated human diseases. The pursuit of efficient diagnostic and treatment...

Altered Nigral Amide Proton Transfer Imaging Signal Concordant With Motor Asymmetry in Parkinson's Disease: A Multipool CEST MRI Study.

Asymmetry is a natural characteristic of Parkinson's disease (PD), which can be used to distinguish PD from atypical parkinsonism. Chemical exchange saturation transfer (CEST) has demonstrated value in reflecting the subtle changes related to neuron loss and abnormal protein accumulation in PD but has not been used to investigate asymmetry in PD. This study aimed to examine asymmetrical changes in the mesencephalic nucleus of PD patients with motor asymmetry using four-pool CEST analysis and to explore the relationship between imaging asymmetry and motor asymmetry. Forty-six PD cases with motor asymmetry (PD_MA) and 23 normal controls (NC) were included. The patients were divided into three subgroups based on their conditions: PD with mild motor asymmetry (PD_MMA), PD with severe motor asymmetry (PD_SMA), and hemiparkinsonism (PD_Hemi). Differences among the more affected and less affected sides of cases in various PD subgroups and the NC group were analyzed. Motor laterality and imaging laterality were determined to evaluate the concordance. Motor asymmetry and imaging asymmetry indexes were calculated to evaluate the correlation. Compared with NC, amide proton transfer (APT) was significantly decreased in the more affected sides of substantia nigra (SN) and red nucleus in the PD_MA, PD_SMA, and PD_Hemi groups. In the PD-SMA group, the APT signal in the SN was significantly reduced in the more affected side compared with the less affected side. The imaging asymmetry index in APT for the SN was positively associated with the motor asymmetry index in the PD_SMA group (β = 0.431, p = 0.014). The imaging laterality in APT for the SN had a significant consistency with motor laterality in the PD_SMA group (κ = 0.566, p = 0.001). These findings suggest inherent asymmetry of APT signal in the SN in PD patients with severe asymmetry, with nigral APT potentially serving as a noninvasive biomarker of lateralization in PD.

Disruption of RNA-binding proteins in neurological disorders.

RNA-binding proteins (RBPs) are multifunctional proteins essential for the regulation of RNA processing and metabolism, contributing to the maintenance of cell homeostasis by modulating the expression of target genes. Many RBPs have been associated with neuron-specific processes vital for neuronal development and survival. RBP dysfunction may result in aberrations in RNA processing, which subsequently initiate a cascade of effects. Notably, RBPs are involved in the onset and progression of neurological disorders via diverse mechanisms. Disruption of RBPs not only affects RNA processing, but also promotes the abnormal aggregation of proteins into toxic inclusion bodies, and contributes to immune responses that drive the progression of neurological diseases. In this review, we summarize recent discoveries relating to the roles of RBPs in neurological diseases, discuss their contributions to such conditions, and highlight the unique functions of these RBPs within the nervous system.

Metabolic Dysfunction in Parkinson's Disease: Unraveling the Glucose-Lipid Connection.

Despite many years of research into the complex neurobiology of Parkinson's disease, the precise aetiology cannot be pinpointed down to one causative agent but rather a multitude of mechanisms. Current treatment options can alleviate symptomsbut only slightly slow down the progression and not cure the disease and its underlying causes. Factors that play a role in causing the debilitating neurodegenerative psycho-motoric symptoms include genetic alterations, oxidative stress, neuroinflammation, general inflammation, neurotoxins, iron toxicity, environmental influences, and mitochondrial dysfunction. Recent findings suggest that the characteristic abnormal protein aggregation of alpha-synuclein and destruction of substantia nigra neurons might be due to mitochondrial dysfunction related to disturbances in lipid and glucose metabolism along with insulin resistance. The latter mechanism of action might be mediated by insulin receptor substrate docking to proteins that are involved in neuronal survival and signaling related to cell destruction. The increased risk of developing Type 2 Diabetes Mellitus endorses a connection between metabolic dysfunction and neurodegeneration. Here, we explore and highlight the potential role of glycolipid cellular insults in the pathophysiology of the disorder, opening up new promising avenues for the treatment of PD. Thus, antidiabetic drugs may be employed as neuromodulators to hinder the progression of the disorder.

Review of Alzheimer's disease and treatments

Alzheimer's disease (AD) is a neurodegenerative disease that primarily affects older adults and is characterized by progressive memory loss and cognitive dysfunction. The disease is the most common type of dementia worldwide and imposes a significant burden on patients, families and society. More than 50 million people worldwide are affected by Alzheimer's disease, placing enormous financial strain on healthcare systems and families. The main molecular metabolic pathways of Alzheimer's disease include amyloid beta protein metabolic pathway and tau protein phosphorylation pathway. Abnormal accumulation of amyloid beta protein in the brain to form plaques, and excessive phosphorylation of tau protein to form neurofibrillary tangles, these pathological changes lead to nerve cell damage and death, resulting in the gradual loss of cognitive function. Current treatments can only slow the progression of the disease or alleviate symptoms and cannot completely cure AD. Finding effective treatment and intervention strategies can not only significantly improve the quality of life of Alzheimer's patients, but also reduce the burden of the disease on society and families. This article will review the background and epidemiology of Alzheimer's disease, discuss its main molecular metabolic pathways in detail, and review the current status of treatment, with a view to providing references for future research and treatment strategies.

Plasma circulating cell-free DNA integrity and relative telomere length as diagnostic biomarkers for Parkinson's disease and multiple system atrophy: a cross-sectional study.

In clinical specialties focusing on neurological disorders, there is a need for comprehensive and integrated non-invasive, sensitive, and specific testing methods. Both Parkinson's disease and multiple system atrophy are classified as α-synucleinopathies, characterized by abnormal accumulation of α-synuclein protein, which provides a shared pathological background for their comparative study. In addition, both Parkinson's disease and multiple system atrophy involve neuronal death, a process that may release circulating cell-free DNA (cfDNA) into the bloodstream, leading to specific alterations. This premise formed the basis for investigating cell-free DNA as a potential biomarker. Cell-free DNA has garnered attention for its potential pathological significance, yet its characteristics in the context of Parkinson's disease and multiple system atrophy are not fully understood. This study investigated the total concentration, nonapoptotic level, integrity, and cell-free DNA relative telomere length of cell-free DNA in the peripheral blood of 171 participants, comprising 76 normal controls, 62 patients with Parkinson's disease, and 33 patients with multiple system atrophy. In our cohort, 75.8% of patients with Parkinson's disease (stage 1-2 of Hoehn & Yahr) and 60.6% of patients with multiple system atrophy (disease duration less than 3 years) were in the early stages. The diagnostic potential of the cell-free DNA parameters was evaluated using receiver operating characteristic (ROC) analysis, and their association with disease prevalence was examined through logistic regression models, adjusting for confounders such as age, sex, body mass index, and education level. The results showed that cell-free DNA integrity was significantly elevated in both Parkinson's disease and multiple system atrophy patients compared with normal controls (P < 0.001 for both groups), whereas cell-free DNA relative telomere length was markedly shorter (P = 0.003 for Parkinson's disease and P = 0.010 for multiple system atrophy). Receiver operating characteristic analysis indicated that both cell-free DNA integrity and cell-free DNA relative telomere length possessed good diagnostic accuracy for differentiating Parkinson's disease and multiple system atrophy from normal controls. Specifically, higher cell-free DNA integrity was associated with increased risk of Parkinson's disease (odds ratio [OR]: 5.72; 95% confidence interval [CI]: 1.54-24.19) and multiple system atrophy (OR: 10.10; 95% CI: 1.55-122.98). Conversely, longer cell-free DNA relative telomere length was linked to reduced risk of Parkinson's disease (OR: 0.16; 95% CI: 0.04-0.54) and multiple system atrophy (OR: 0.10; 95% CI: 0.01-0.57). These findings suggest that cell-free DNA integrity and cell-free DNA relative telomere length may serve as promising biomarkers for the early diagnosis of Parkinson's disease and multiple system atrophy, potentially reflecting specific underlying pathophysiological processes of these neurodegenerative disorders.

Mechanisms of Neurosyphilis-Induced Dementia: Insights into Pathophysiology.

Neurosyphilis-induced dementia represents a severe manifestation of tertiary syphilis, characterized by cognitive and neuropsychiatric impairments. This condition arises from the progression of syphilis to the central nervous system, where the spirochete causes damage through invasion, chronic inflammation, and neurodegeneration. The pathophysiology involves chronic inflammatory responses, direct bacterial damage, and proteinopathies. Treponema pallidum triggers an inflammatory cascade, resulting in neuronal injury and synaptic dysfunction. Abnormal protein accumulations, including TAR DNA-binding protein 43 (TDP-43) and tau, contribute to neuronal loss and cognitive decline. Seizures, psychiatric symptoms, and motor deficits further complicate the progression of dementia. Diagnosis includes clinical assessment, cerebrospinal fluid analysis, and neuroimaging. Diagnostic tests include CSF-VDRL, FTA-ABS, and neuroimaging techniques such as MRI and PET scans, which help detect structural changes and confirm neurosyphilis. Management of neurosyphilis-induced dementia involves antibiotic therapy and psychotropic medications to address both infectious and symptomatic components. While penicillin remains the cornerstone of treatment, psychotropic agents, including haloperidol, risperidone, quetiapine, and divalproex sodium, can manage psychiatric symptoms. However, careful monitoring is required due to potential side effects and interactions with ongoing treatment. Overall, early diagnosis and comprehensive management are crucial for mitigating the cognitive and neuropsychiatric impairments associated with neurosyphilis-induced dementia.

Dual-Carbon Dots Composite: A Multifunctional Photo-Propelled Nanomotor Against Alzheimer's β-Amyloid.

The abnormal accumulation of β-amyloid protein (Aβ) is considered as the main pathological hallmark of Alzheimer's disease (AD). The design of potent multifunctional theranostic agents targeting Aβ is one of the effective strategies for AD prevention and treatment. Nanomotors as intelligent, advanced, and multifunctional nanoplatforms can perform many complex tasks, but their application in AD theranostics is rare. Herein, sub-10nm multifunctional dual-carbon dots composites (ERCD) with photo-propelled nanomotor behavior are fabricated by conjugating near-infrared (NIR) carbon dots (RCD) of thermogenic and photodynamic capability with the previously reported epigallocatechin gallate-derived carbonized polymer dots (ECD). ERCD-1 (ECD:RCD = 1:2.5) showed potent inhibitory capability similar to ECD in the absence of NIR light, and exhibited photooxygenation activity and nanomotor behavior powered by "self-thermophoretic force" under NIR irradiation, significantly enhancing the inhibition, disaggregation, and photooxygenation capabilities. The nanomotor suppressed Aβ fibrillization and rapidly disaggregated mature Aβ fibrils at very low concentrations (0.5µg mL-1). Moreover, the NIR-activated ERCD-1 imaged Aβ plaques in vivo and prolonged nematode lifespan by 6 d at 2µg mL-1. As a proof-of-concept, this work opened a new avenue to the design of multifunctional sub-10nm nanomotors targeting Aβ for AD theranostics.

Mechanistic exploration of ubiquitination-mediated pathways in cerebral ischemic injury.

The ubiquitin-proteasome system (UPS) plays a pivotal role in regulating protein homeostasis and cellular processes, including protein degradation, trafficking, DNA repair, and cell signaling. During cerebral ischemia, ischemic conditions profoundly disrupt UPS activity, leading to proteasomal dysfunction and the accumulation of abnormal proteins. This imbalance contributes to neuronal injury and cell death observed in ischemic stroke. The UPS is intricately linked to various signaling pathways crucial for neuronal survival, inflammation, and cellular stress response, such as NF-κB, TRIM, TRIP, JAK-STAT, PI3K/Akt, and ERK1/2. Alterations in the ubiquitination process can significantly impact the activation and regulation of these pathways, exacerbating ischemic brain injury. Therapeutic approaches targeting the UPS in cerebral ischemia aim to rebalance protein levels, reduce proteotoxic stress, and mitigate neuronal injury. Strategies include proteasome inhibition, targeting specific ubiquitin ligases and deubiquitinating enzymes, and modulating ubiquitination-mediated regulation of key signaling pathways implicated in ischemia-induced pathophysiology. Therefore, the present review discusses the molecular mechanisms underlying UPS dysfunction in ischemic stroke is crucial for developing effective therapeutic interventions. Modulating ubiquitination-mediated pathways through therapeutic interventions targeting specific UPS components holds significant promise for mitigating ischemic brain injury and promoting neuroprotection and functional recovery in patients with cerebral ischemia.

Skin and Induced Pluripotent Stem Cells as Biomarkers for Neurodegenerative Diseases.

As the global population ages, the rising prevalence of neurodegenerative diseases, characterized by abnormal protein aggregates, presents significant challenges for early diagnosis and disease monitoring. Identifying accessible tissue biomarkers is crucial for advancing our ability to detect and track the progression of these diseases. Among the most promising biomarkers is the skin, which shares a common embryological origin with the brain and central nervous system (CNS). This biological connection positions the skin as a potential reflection of CNS pathology. Over the past decades, gene expression studies have demonstrated that key genes involved in neurodegenerative diseases are also expressed in skin tissues. Genes such as APP, PSEN1, PPA2, PINK1, LRRK2, PLCB4, MAPT, SPAST, and SPG7 are prominent in this regard. Beyond gene expression, proteins related to neurodegenerative diseases-such as α-synuclein, TAU, PARKIN, and prion protein (PrP)-have been isolated from the skin of affected individuals, underscoring the skin's capacity to mirror neural degeneration. This non-invasive window into neurodegenerative processes is further enhanced by advances in stem cell technology, which have allowed for the generation of human-induced pluripotent stem cells (iPSCs) from patient-derived fibroblasts. These iPSCs offer a valuable model for studying disease mechanisms and developing therapeutic approaches. This review conducts a comprehensive analysis of the literature from databases such as PubMed, Google Scholar, and ResearchGate, emphasizing the unique potential of the skin as a non-invasive biomarker for neurodegenerative diseases. It explores how the skin serves as a bridge between gene expression and disease pathology in both the skin and the CNS. By leveraging this biological connection, the skin emerges as a promising model for enhancing our understanding of neurodegenerative disorders and developing innovative strategies for early detection and treatment. However, significant limitations remain, requiring further validation to establish the specificity and sensitivity of these biomarkers.

Liquid-liquid phase separation of Tau and α-synuclein: a new pathway of overlapping neuropathologies

Liquid-liquid phase separation (LLPS) is a critical phenomenon that leads to the formation of liquid-like membrane-less organelles within cells. Advances in our understanding of condensates reveal their significant roles in biology and highlight how their dysregulation may contribute to disease. Recent evidence indicates that the high protein concentration in coacervates may lead to abnormal protein aggregation associated with several neurodegenerative diseases. The presence of condensates containing multiple amyloidogenic proteins may play a role in the co-deposition and comorbidity seen in neurodegeneration. This review first provides a brief overview of the physicochemical bases and molecular determinants of LLPS. It then summarizes our understanding of Tau and α-synuclein (AS) phase separation, key proteins in Alzheimer’s and Parkinson´s diseases. By integrating recent findings on complex Tau and AS coacervation, this article offers a fresh perspective on how LLPS may contribute to the pathological overlap in neurodegenerative disorders and provide a novel therapeutic target to mitigate or prevent such conditions.

Upregulating ANKHD1 in PS19 mice reduces Tau phosphorylation and mitigates Tau-toxicity-induced cognitive deficits.

Abnormal accumulation of Tau protein in the brain disrupts normal cellular function and leads to neuronal death linked with many neurodegenerative disorders such as Alzheimer's disease. An attractive approach to mitigate Tau-induced neurodegeneration is to enhance the clearance of toxic Tau aggregates. We previously showed that upregulation of the fly gene mask protects against FUS- and Tau-induced photoreceptor degeneration in fly disease models. Here we have generated a transgenic mouse line carrying Cre-inducible ANKHD1, the mouse homolog of mask, to determine whether the protective role of mask is conserved from flies to mammals. Utilizing the TauP301S-PS19 mouse model for Tau-related dementia, we observed that ANKHD1 significantly reduced hyperphosphorylated human Tau in 6-month-old mice. Additionally, there was a notable trend towards reduced gliosis levels in these mice, suggesting a protective role of ANKHD1 against TauP301S-linked degeneration. Further analysis of 9-month-old mice revealed a similar trend of effects. Moreover, we found that ANKHD1 also suppresses the cognitive defect of 9-month-old PS19 female mice in novel object recognition (NOR) behavioral assay. Unlike previous therapeutic strategies that primarily focus on inhibiting Tau phosphorylation or directly clearing aggregates, this study highlights the novel role of ANKHD1 in promoting autophagy as a means to mitigate Tau pathology. This novel mechanism not only underscores ANKHD1's potential as a unique therapeutic target for tauopathies but also provides new insights into autophagy-based interventions for neurodegenerative diseases.

Drug Discovery and Screening Tool Development for Tauopathies by Focusing on Pathogenic Tau Repeat 3 Oligomers.

Comprehending early amyloidogenesis is essential for the development of effective therapeutic strategies. In tauopathies like Alzheimer's disease (AD), the abnormal accumulation of tau protein is initiated by pathological tau seeds. Mounting evidence implies that the microtubule binding domain, consisting of three to four repeats, plays a pivotal role in this process, yet the exact region driving the formation of pathogenic species needs to be further scrutinized. Here, we chemically synthesized individual tau repeats to identify those exhibiting pathogenic prion-like characteristics. Notably, repeat 3 (R3) displayed a remarkable propensity to polymerize, form toxic filaments, and induce cognitive impairment, even in the absence of an aggregation-promoting inducer, highlighting its physiological relevance. Additionally, oligomeric R3 was identified as a particularly pathological form, prompting the establishment of a screening platform. Through screening, tolcapone was found to possess therapeutic efficacy against pathological tau aggregates in PS19 transgenic mice. This screening platform provides a valuable avenue for identifying compounds that selectively interact with peptides implicated in the progression of tauopathies.

A novel homozygous PSAP mutation identified by whole exome sequencing in a consanguineous family with metachromatic leukodystrophy: a case report.

Metachromatic leukodystrophy (MLD) is a genetic lysosomal disease. Here, we investigated the role of prosaposin (PSAP) gene mutations in MLD. This current case report describes a female patient who presented with motor development regression at two years and five months of age. The symptoms included difficulty walking, loss of ambulation, increased muscle tension, limb pain, and intentional tremors. Brain magnetic resonance imaging revealed potential white matter lesions, while electromyography indicated neurogenic damage in both lower limbs. Gesell assessment showed severe motor retardation, along with mild retardation in adaptability, speech, and social communication. Whole exome sequencing analysis identified a homozygous mutation in the PSAP gene, specifically c.643A>G, resulting in the amino acid change p.N215D. Immunofluorescence assays of cultured cells indicated no impact on the PSAP protein lysosomal localization, but the mutation was associated with a decreased lysosomal pH and reduced cathepsin D activity. Transmission electron microscopy revealed changes in lysosome morphology and abnormal protein aggregation. These findings suggest that the PSAP c.643A>G (p.N215D) mutation may be a causal factor for MLD in this patient. This discovery may provide new insights into the genetic basis and pathophysiological mechanisms of MLD.

Copper Overload Promotes β-amyloid Induced NLRP3/Caspase-1/GSDMD-Mediated Pyroptosis in Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by cognitive decline and abnormal protein accumulation. Copper imbalance and pyroptosis play significant roles in the pathogenesis of AD. Recent studies have suggested that dysregulated copper homeostasis contributed to β-amyloid accumulation, which may activate the NOD-like receptor protein 3 (NLRP3)-related pyroptosis pathway, promoting neuronal damages and AD progression. Therefore, the present study aims to investigates whether copper facilitates AD through exacerbating β-amyloid (Aβ) induced activation of NLRP3/Caspase-1/Gasdermin D (GSDMD)-mediated neuronal cell pyroptosis. Mouse hippocampal HT-22 cells were cultured with Aβ1-42 oligomer for 24 h as AD Model group. CuCl2 treatment was administered to the AD cell model, and cell survivability levels were detected by Cell Counting Kit-8 (CCK-8), TdT-mediated dUTP nick end labeling (TUNEL), and other relevant kits. Mitochondrial function was evaluated using Mitochondrial membrane potential dye JC-1 and transmission electron microscopy (TEM). After intervention with the NLRP3 inhibitor MCC950, activation of the NLRP3/Caspase-1/GSDMD pathway by copper ions (Cu2+) was confirmed via Western Blot. Thioredoxin T (ThT) fluorescence assay was performed to observe the aggregation effect of Aβ induced by Cu2+ overload. CuCl2 treatment of the AD cell model resulted in up-regulation of the levels of Lactate Dehydrogenase (LDH), Interleukin-1β (IL-1β), and IL-18 expression, which indicated activation of pyroptosis. We observed a significant decrease in mitochondrial membrane potential, mitochondrial swelling, and loss of mitochondrial cristae by fluorescence microscopy and TEM. ThT fluorescence imaging showed that Cu2+ promoted Aβ aggregation and up-regulated NLRP3, apoptosis-associated speck-like protein containing a CARD (ACS), Caspase-1, Cleaved Caspase-1, GSDMD, and Gasdermin D N-terminal (GSDMD-NT). The NLRP3 inhibitor MCC950 partially reversed Cu2+-mediated pyroptosis in HT-22 cells. Exposure to copper ions disrupt mitochondrial copper homeostasis, promotes Aβ aggregation, and activates NLRP3 inflammasomes, further promoting the Aβ aggregation activated pyroptosis in AD cell models.

Targeting Protein Aggregation in ALS.

Proteinopathies involve the abnormal accumulation of specific proteins. Maintaining the balance of the proteome is a finely regulated process managed by a complex network of cellular machinery responsible for protein synthesis, folding, and degradation. However, stress and ageing can disrupt this balance, leading to widespread protein aggregation. Currently, several therapies targeting protein aggregation are in clinical trials for ALS. These approaches mainly focus on two strategies: addressing proteins that are prone to aggregation due to mutations and targeting the cellular mechanisms that maintain protein homeostasis to prevent aggregation. This review will cover these emerging drugs. Advances in ALS research not only offer hope for better outcomes for ALS patients but also provide valuable insights and methodologies that can benefit the broader field of neurodegenerative disease drug discovery.