ACS Chemical Neuroscience最新文献_第5页

Grueneberg Ganglion: An Unexplored Site for Intranasal Drug Delivery in Alzheimer’s Disease 格林伯格神经节：阿尔茨海默病鼻内给药的一个未开发的部位。

IF 3.9 3区医学

ACS Chemical Neuroscience Pub Date : 2025-09-04 DOI: 10.1021/acschemneuro.5c00376

Violina Kakoty, Ji Hee Kang, O Hyun Lee, Da Hee Oh and Young Tag Ko*,

{"title":"Grueneberg Ganglion: An Unexplored Site for Intranasal Drug Delivery in Alzheimer’s Disease","authors":"Violina Kakoty, Ji Hee Kang, O Hyun Lee, Da Hee Oh and Young Tag Ko*, ","doi":"10.1021/acschemneuro.5c00376","DOIUrl":"10.1021/acschemneuro.5c00376","url":null,"abstract":"Neurological disorders such as Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis pose significant challenges for treatment. Reasons for the difficulty in finding cures for these conditions include complications in early diagnosis, progressive and irreversible neuronal damage, and the presence of the blood–brain barrier (BBB), which hinders the delivery of drugs to the affected areas of the brain. Intranasal (INL) drug administration has increasingly gained popularity among researchers for targeting neurological conditions, because of its ability to bypass the BBB. However, chronic INL administration leads to nasal mucosa irritation. Additionally, rapid mucociliary clearance, a lack of targeted drug delivery, increased enzymatic degradation, and tight junctions that obstruct drug transport limit the clinical applicability of the INL route. To overcome these challenges, a unique region in the rodent nose, known as the Grueneberg Ganglion (GG), can be considered to be a novel site for INL drug administration. GG is a small structure housed under the snout cartilage of the nasal septum, approximately 1.5 mm from the nasal opening in mice. It is directly connected to the main olfactory bulb through axons. This Perspective aims to expand knowledge on why GG may be a viable option for INL delivery to combat neurological conditions. For better understanding, we have explained the INL administration in GG, using Alzheimer’s Disease and INL insulin therapy as a role model for the current review.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 18","pages":"3425–3437"},"PeriodicalIF":3.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bidirectional Relationship between the BDNF Gene and miRNA: Implications for PD Pathogenesis BDNF基因与miRNA的双向关系：PD发病机制的意义

IF 3.9 3区医学

ACS Chemical Neuroscience Pub Date : 2025-09-03 DOI: 10.1021/acschemneuro.5c00173

Ajay Elangovan, Mahalaxmi Iyer, Dibbanti HariKrishna Reddy, Arvinder Wander, Masako Kinoshita, Jayalaskhmi Krishnan and Balachandar Vellingiri*,

{"title":"Bidirectional Relationship between the BDNF Gene and miRNA: Implications for PD Pathogenesis","authors":"Ajay Elangovan, Mahalaxmi Iyer, Dibbanti HariKrishna Reddy, Arvinder Wander, Masako Kinoshita, Jayalaskhmi Krishnan and Balachandar Vellingiri*, ","doi":"10.1021/acschemneuro.5c00173","DOIUrl":"10.1021/acschemneuro.5c00173","url":null,"abstract":"Parkinson’s disease (PD) is a neurological degenerative condition that primarily affects older people. Although reduced motor skills, stiffness, dyslexia, and other motor symptoms predominate in PD, the nonmotor symptoms, such as cognitive impairment, also play an important part in the PD-affected brain. Studies have reported that the brain-derived neurotrophic factor (BDNF) has a pivotal role in monitoring the nonmotor symptoms of PD. The receptor of BDNF, which is tropomyosin-related kinase (BDNF/TrkB), is prominently dispersed in the substantia nigra region, where the presence of dopaminergic (DAergic) neurons is dense. This shows that the BDNF/TrkB receptor promotes the maintenance, protection, and plasticity of neurons in the brain. Studies have reported that the expression of BDNF/TrkB is found to be downregulated, which significantly elevates the impairments related to cognition. Reports also suggest that miRNAs belong to the class of long noncoding RNA (LncRNAs) and have a critical role in the development and maintenance of neurons, especially dopaminergic neurons (DAergic neurons). Interestingly, it is found that LncRNA BDNF-AS also causes PD pathogenesis by regulating the neurotrophin signaling pathway associated with BDNF and its miRNA targets. This evidence suggests that BDNF could have a dual role in PD, which is a protector as well as a modulator for DAergic neurons in the PD brain. Therefore, in this review, we depict the important roles of the BDNF gene, its receptors, and LncRNA BDNF-AS in causing PD pathogenesis. Also, we suggest how miRNA targets could act as a potential remedy for PD.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 18","pages":"3411–3424"},"PeriodicalIF":3.9,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Overexpression of BDNF by Astrocytes Targeted Delivery of mRNA Ameliorates Cognitive Impairment in Mouse Model of TBI 星形胶质细胞靶向递送mRNA过表达BDNF可改善脑外伤小鼠模型的认知功能障碍。

IF 3.9 3区医学

ACS Chemical Neuroscience Pub Date : 2025-09-03 DOI: 10.1021/acschemneuro.5c00505

Ruijun Wang, Hangai Bai, Dezhi Yang, Wuhanqimuge, Shuang Bai, Hai Xiao*, Huricha Baigude* and Naikang Gao*,

{"title":"Overexpression of BDNF by Astrocytes Targeted Delivery of mRNA Ameliorates Cognitive Impairment in Mouse Model of TBI","authors":"Ruijun Wang, Hangai Bai, Dezhi Yang,  Wuhanqimuge, Shuang Bai, Hai Xiao*, Huricha Baigude* and Naikang Gao*, ","doi":"10.1021/acschemneuro.5c00505","DOIUrl":"10.1021/acschemneuro.5c00505","url":null,"abstract":"Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic development and plasticity. It is a promising therapeutic target for improving neurofunctional outcomes after traumatic brain injury (TBI). However, the delivery of BDNF faces several significant challenges including limited entry into the CNS due to blood-brain barrier (BBB), short half-life, and potential side effects. The use of viral vectors like AAV to deliver the BDNF gene directly to the brain has shown promise in animal models. However, issues with host immunogenicity and limited biodistribution remain. Herein, we report a successful restoration of cognitive function of a TBI mouse model by efficient delivery of BDNF mRNA loaded to a novel lipid nanoparticle (DA6 LNP). DA6 LNPs loaded with either luciferase mRNA or GFP mRNA were internalized by astrocytes and dose dependently expressed the corresponding protein. Two consecutive intravenous injections of DA6 LNPs loaded with BDNF mRNA to a TBI mouse model resulted in overexpression of BDNF in the brain and ameliorated cognitive impairment. Collectively, our data suggested that DA6 LNP is a promising carrier for CNS targeted delivery of therapeutic RNAs.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 18","pages":"3465–3471"},"PeriodicalIF":3.9,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144990944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mathematical Modeling of Aβ-42 Dimerization Dynamics: Integrating Physics-Based Simulations, Graph-Based Variational Autoencoder-Driven Neural Relational Inference, and Chaos Theory Aβ-42二聚化动力学的数学建模：集成基于物理的模拟、基于图的变分自编码器驱动的神经关系推理和混沌理论。

IF 3.9 3区医学

ACS Chemical Neuroscience Pub Date : 2025-09-02 DOI: 10.1021/acschemneuro.5c00201

Ehsan Sayyah*, Emel Kurul, Hüseyin Tunç and Serdar Durdağı*,

{"title":"Mathematical Modeling of Aβ-42 Dimerization Dynamics: Integrating Physics-Based Simulations, Graph-Based Variational Autoencoder-Driven Neural Relational Inference, and Chaos Theory","authors":"Ehsan Sayyah*, Emel Kurul, Hüseyin Tunç and Serdar Durdağı*, ","doi":"10.1021/acschemneuro.5c00201","DOIUrl":"10.1021/acschemneuro.5c00201","url":null,"abstract":"Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the pathological aggregation of amyloid-beta (Aβ) peptides, particularly Aβ-42, which plays a central role in disease progression. Soluble Aβ dimers have been implicated as the primary neurotoxic species contributing to synaptic dysfunction and cognitive impairment. In this study, we employ a comprehensive computational framework integrating molecular dynamics (MD) simulations, neural relational inference (NRI) modeling, and largest Lyapunov exponent (LLE) analysis to elucidate the molecular mechanisms underlying Aβ-42 dimerization and evaluate the inhibitory potential of small molecules, apigenin and caffeine. Our findings demonstrate that apigenin exhibits a stronger inhibitory effect on Aβ-42 aggregation compared to caffeine. MD simulations reveal that apigenin disrupts monomer–monomer interactions by destabilizing key aggregation-prone regions, particularly residues 29 and 30, as quantified by MM/GBSA binding-free energy calculations. The application of NRI modeling further confirms the role of apigenin in reducing residue–residue interaction strength, thereby preventing the formation of stable β-sheet structures. Additionally, LLE analysis highlights the ability of apigenin to mitigate chaotic fluctuations within Aβ-42 dynamics, stabilizing monomeric conformations while preventing dimerization. By integrating computational biophysics and mathematical modeling approaches, this study provides a novel mechanistic understanding of Aβ-42 aggregation and offers compelling evidence for apigenin as a promising therapeutic candidate for AD. These findings underscore the potential of natural small molecules in targeting early-stage Aβ-42 aggregation, paving the way for future experimental and clinical investigations.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 18","pages":"3513–3526"},"PeriodicalIF":3.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

New Insights into the Structural Rearrangement and Aggregation Properties of Aβ-PrP Cross-Seeding Modulated by Histidine Behaviors 组氨酸行为对a - β- prp交叉播种结构重排和聚集特性的新认识

IF 3.9 3区医学

ACS Chemical Neuroscience Pub Date : 2025-09-02 DOI: 10.1021/acschemneuro.5c00462

Jing Li, Yue Sun, Lisha Wang, Hancheng Gong and Hu Shi*,

{"title":"New Insights into the Structural Rearrangement and Aggregation Properties of Aβ-PrP Cross-Seeding Modulated by Histidine Behaviors","authors":"Jing Li, Yue Sun, Lisha Wang, Hancheng Gong and Hu Shi*, ","doi":"10.1021/acschemneuro.5c00462","DOIUrl":"10.1021/acschemneuro.5c00462","url":null,"abstract":"Histidine behavior plays a pivotal role in protein folding and misfolding; yet, its influence on cross-seeding during the nucleation phase remains poorly understood. The current study investigates the role of histidine behavior on the structural and aggregation properties during the cross-seeding of Aβ(1–40) and PrP(106–126) peptides. Our findings reveal that all systems tend to form dimeric structures. Antiparallel β-sheet structures predominate in both Aβ and PrP chains across all systems, particularly in the Aβ regions L17-E22, K28–I31, and G33-V39 (except (εεεδ)) and the PrP regions T43-H47 and A52-L61. We found that Aβ and PrP mutually promote structural rearrangement during cross-seeding, forming stable dimers. H-bond analysis confirmed that H6, H13, H14, and H47 are directly involved in H-bond networks, confirming that the histidine behavior plays a critical role in modulating these processes. Our further analysis shows that all systems exhibit characteristic four/five β-strand structures, forming regularly arranged β-strands among the N-termini, CHC, and C-terminus in Aβ, as well as T43-H47 and A52-L61 in PrP. Furthermore, two stacking modes were discussed in our studies. These findings provide mechanistic insights into histidine’s role in amyloid aggregation and highlight the significance of Aβ-PrP cross-seeding interactions in amyloidogenesis, offering potential therapeutic targets for protein misfolding diseases.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 18","pages":"3567–3576"},"PeriodicalIF":3.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neuroprotective Effects of a 3-Amino Quinazoline Derivative via Keap1–Nrf2 Pathway Activation in an ICV-STZ-Induced Rat Model of Sporadic Alzheimer’s Disease 3-氨基喹唑啉衍生物通过Keap1-Nrf2通路激活对散发性阿尔茨海默病大鼠模型的神经保护作用

IF 3.9 3区医学

ACS Chemical Neuroscience Pub Date : 2025-09-01 DOI: 10.1021/acschemneuro.5c00540

Pranav Maheta, Chirag Patel*, Dharmishtha Parmar, Jayesh Beladiya, Sandip Patel, Devang Sheth and Sandip Dholakia,

{"title":"Neuroprotective Effects of a 3-Amino Quinazoline Derivative via Keap1–Nrf2 Pathway Activation in an ICV-STZ-Induced Rat Model of Sporadic Alzheimer’s Disease","authors":"Pranav Maheta, Chirag Patel*, Dharmishtha Parmar, Jayesh Beladiya, Sandip Patel, Devang Sheth and Sandip Dholakia, ","doi":"10.1021/acschemneuro.5c00540","DOIUrl":"10.1021/acschemneuro.5c00540","url":null,"abstract":"The Keap1-Nrf2 pathway has emerged as a promising target for Alzheimer’s disease (AD). This study employed in silico modeling to identify Nrf2 activators through Keap1 inhibition. The most promising quinazoline derivative, LMDP10, was then evaluated in a rat model of sporadic AD induced by Intracerebroventricular (ICV) streptozotocin (STZ). ICV STZ-induced rats were treated with LMDP10 (5–50 mg/kg, orally). Behavioral changes were assessed using the Morris water maze (MWM) and novel object recognition (NOR) tests. Additionally, neurochemical marker (oxidant/antioxidant), proinflammatory cytokine (TNF-α) levels, Nrf2 levels, and histopathological alterations were analyzed in both the hippocampus and cortex. An oral toxicity study of LMDP10 was performed according to the OECD Guideline 425. LMDP10 treatment (50 mg/kg/day) significantly improved memory performance (increased percentage time spent in target quadrant in the MWM test and increased discrimination index in the NOR test; P < 0.001 for both). Notably, this dose also significantly increased Nrf2, SOD, and GSH levels while attenuating elevated MDA and TNF-α levels in both brain regions compared to those in vehicle-treated STZ rats. LMDP10 emerged as a potential therapeutic candidate for AD. LMDP10 improved memory function and increased Nrf2 signaling and antioxidant defenses while reducing neuroinflammation. These findings suggest that the neuroprotective effects of LMDP10 may involve Keap1-Nrf2 pathway activation, warranting further investigation of its therapeutic potential in AD.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 18","pages":"3611–3622"},"PeriodicalIF":3.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synaptotagmin III Plays a Protective Role in Neonatal Multiple Sevoflurane Exposure-Induced Cognitive Deficits in Mice Synaptotagmin III在新生儿多重七氟醚暴露诱导的小鼠认知缺陷中起保护作用

IF 3.9 3区医学

ACS Chemical Neuroscience Pub Date : 2025-09-01 DOI: 10.1021/acschemneuro.5c00537

Yutong Gao, Ting Wu and Xiangdi Yu*,

{"title":"Synaptotagmin III Plays a Protective Role in Neonatal Multiple Sevoflurane Exposure-Induced Cognitive Deficits in Mice","authors":"Yutong Gao, Ting Wu and Xiangdi Yu*, ","doi":"10.1021/acschemneuro.5c00537","DOIUrl":"10.1021/acschemneuro.5c00537","url":null,"abstract":"General anesthesia in infants and young children raises concerns about potential neurodevelopmental effects, as anesthetics such as sevoflurane may impair cognitive function and increase neuroinflammation. Synaptotagmin 3 (Syt3), a protein involved in synaptic regulation, has been identified as a possible modulator of these effects. This study explores the role of Syt3 in mitigating cognitive and inflammatory outcomes following neonatal sevoflurane exposure in mice. To this end, neonatal wild-type (WT) and Syt3 knockout (Syt3–/–) C57BL/6 mice were exposed to 3% sevoflurane for 2 h daily on postnatal days 7–9. Syt3 protein levels in the hippocampus were measured postexposure using Western blot and ELISA. Neuroinflammatory markers (IL-1β, TNF-α, and MCP-1) were quantified by ELISA, and cognitive function was assessed using object location memory and novel object recognition tasks. Anxiety-like behavior was evaluated with the elevated plus maze. Syt3 overexpression was achieved in WT mice by using CRISPR activation plasmids. Our results indicated that sevoflurane exposure reduced Syt3 levels in the hippocampus of WT mice, correlated with heightened neuroinflammation and cognitive deficits. Syt3–/– mice exhibited exacerbated cognitive impairment, increased inflammation, and more severe anxiety-like behavior. Overexpression of Syt3 in WT mice mitigated these effects, improving cognitive function, reducing inflammation, and alleviating anxiety-like behavior. Syt3 protects against sevoflurane-induced cognitive and inflammatory impairments in neonatal mice. These findings suggest Syt3 as a potential therapeutic target for reducing neurodevelopmental risks associated with pediatric anesthesia.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 18","pages":"3603–3610"},"PeriodicalIF":3.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Developing Intravenous Delivery of Water-Soluble Prodrugs of Idebenone for the Treatment of Acute Ischemic Stroke 静脉输注水溶性艾地苯酮治疗急性缺血性脑卒中的研究。

IF 3.9 3区医学

ACS Chemical Neuroscience Pub Date : 2025-08-31 DOI: 10.1021/acschemneuro.5c00340

Jian Jia, Huihao Wang, Weiwei Wang, Peng Xie, Ping Li, Peng Jiang, Wei Xie, Li Liu* and Guan Wang*,

{"title":"Developing Intravenous Delivery of Water-Soluble Prodrugs of Idebenone for the Treatment of Acute Ischemic Stroke","authors":"Jian Jia, Huihao Wang, Weiwei Wang, Peng Xie, Ping Li, Peng Jiang, Wei Xie, Li Liu* and Guan Wang*, ","doi":"10.1021/acschemneuro.5c00340","DOIUrl":"10.1021/acschemneuro.5c00340","url":null,"abstract":"Ischemic stroke (IS) represents a substantial global health threat, but only a few effective medicines exist to treat IS, with a huge unmet clinical need. Idebenone (IDB), a coenzyme Q10 analogue, has multitarget effects, including enhancing mitochondrial energy metabolism, scavenging free radicals, and anti-inflammation, which is approved in Europe for treating Leber’s hereditary optic neuropathy (LHON). However, IDB has poor water solubility and oral bioavailability, resulting in insufficient therapeutic plasma concentrations, even following high-dose oral administration, and limiting its use for brain diseases and acute-phase interventions. To address these challenges, we synthesized and identified novel water-soluble IDB prodrugs and found that compound I-7 could adopt intravenous delivery for treating acute IS (AIS) with excellent plasma and brain exposure in normal and IS rats. Besides, I-7 significantly alleviated brain infarct and edema and improved motor function and cerebral blood flow in acute and chronic IS rat models. Compound I-7 is currently undergoing comprehensive evaluation as a preclinical candidate for anti-AIS.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 18","pages":"3541–3553"},"PeriodicalIF":3.9,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modulation of Amyloid-β Aggregation by Surface Proteins from Pathogens Associated with Alzheimer’s Disease 与阿尔茨海默病相关的病原体表面蛋白对淀粉样蛋白-β聚集的调节

IF 3.9 3区医学

ACS Chemical Neuroscience Pub Date : 2025-08-27 DOI: 10.1021/acschemneuro.5c00444

Antonin Kunka, Hana Hribkova, Tereza Vanova, Veronika Pospisilova, Martin Havlasek, Jan Haviernik, Daniel Ruzek, Jiri Damborsky, Dasa Bohaciakova* and Zbynek Prokop*,

{"title":"Modulation of Amyloid-β Aggregation by Surface Proteins from Pathogens Associated with Alzheimer’s Disease","authors":"Antonin Kunka, Hana Hribkova, Tereza Vanova, Veronika Pospisilova, Martin Havlasek, Jan Haviernik, Daniel Ruzek, Jiri Damborsky, Dasa Bohaciakova* and Zbynek Prokop*, ","doi":"10.1021/acschemneuro.5c00444","DOIUrl":"10.1021/acschemneuro.5c00444","url":null,"abstract":"Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder. Despite substantial research efforts, our understanding of its pathogenesis remains incomplete, limiting the development of effective treatments and preventive strategies. The potential role of microbial pathogens in AD etiology has gained increasing attention. Various human microbial pathogens have been identified in the brains of AD patients, leading to the pathogen hypothesis, which posits that these microorganisms may disrupt the brain’s immune regulation and homeostasis. In this study, we examine the effects of proteins from three pathogens, Borrelia burgdorferi, HSV-1, and Porphyromonas gingivalis, on the aggregation of antimicrobial peptide amyloid-β (Aβ). Three of the four studied proteins were found to attenuate the aggregation of Aβ42 by interacting with its soluble form and inhibiting primary and secondary pathways. These in vitro findings were further supported by experiments using mature neurons derived from human pluripotent stem cells, which showed an increased accumulation of amyloid precursor protein (APP) aggregates upon infection with HSV-1 or exposure to the OspA surface protein from B. burgdorferi. Together, our results provide mechanistic insights into how pathogen-associated proteins modulate Aβ42 aggregation, contributing to an understanding of their potential role in AD pathogenesis.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 18","pages":"3554–3566"},"PeriodicalIF":3.9,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.5c00444","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Donepezil and Memantine Derivatives for Dual-Function and Prodrug Applications in Alzheimer’s Disease 多奈哌齐和美金刚衍生物用于阿尔茨海默病的双重功能和前药应用。

IF 3.9 3区医学

ACS Chemical Neuroscience Pub Date : 2025-08-27 DOI: 10.1021/acschemneuro.5c00493

Karna Terpstra, Citlali Gutiérrez, Kai Gui and Liviu M. Mirica*,

{"title":"Donepezil and Memantine Derivatives for Dual-Function and Prodrug Applications in Alzheimer’s Disease","authors":"Karna Terpstra, Citlali Gutiérrez, Kai Gui and Liviu M. Mirica*, ","doi":"10.1021/acschemneuro.5c00493","DOIUrl":"10.1021/acschemneuro.5c00493","url":null,"abstract":"The treatment of Alzheimer’s disease by acetylcholinesterase (AChE) and N-methyl-d-aspartate receptor (NMDAR) inhibitors is limited by the narrow therapeutic window and adverse side effects of the drugs. This study aims to increase the efficacy and limit the side effects of donepezil, an AChE inhibitor, and memantine, an NMDAR inhibitor, through the addition of amyloid-β (Aβ)-targeting fragments to create dual-function compounds. The incorporation of the amyloid-targeting fragments successfully produced compounds with affinity for Aβ fibrils, and that can stain amyloid plaques in the brains of 5xFAD mice. The donepezil-based compounds showed significant changes in AChE inhibition compared to donepezil due to the incorporation of the Aβ-targeting fragment and as confirmed by molecular docking studies. The memantine-derived compound showed good brain uptake in 5xFAD mice but lacked compatibility with NMDAR inhibition based on in vitro assays and molecular docking. Importantly, the memantine-derived compound acts as a prodrug in vivo, releasing memantine within a pharmacologically relevant time frame. Overall, these findings suggest that dual-function compounds may be useful as drug delivery agents that can be metabolized to release an active drug in areas of the brain rich in amyloid plaques and thus could lead to improved treatments for Alzheimer’s disease.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 18","pages":"3591–3602"},"PeriodicalIF":3.9,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0