ACS Chemical Neuroscience最新文献

{"title":"Evaluation of Alpha-Synuclein and Tau Antiaggregation Activity of Urea and Thiourea-Based Small Molecules for Neurodegenerative Disease Therapeutics.","authors":"Susantha K Ganegamage, Taiwo A Ademoye, Henika Patel, Heba Alnakhala, Arati Tripathi, Cuong Calvin Duc Nguyen, Khai Pham, Germán Plascencia-Villa, Xiongwei Zhu, George Perry, Shiliang Tian, Ulf Dettmer, Cristian Lasagna-Reeves, Jessica S Fortin","doi":"10.1021/acschemneuro.4c00282","DOIUrl":"10.1021/acschemneuro.4c00282","url":null,"abstract":"<p><p>Alzheimer's disease (AD) and Parkinson's disease (PD) are multifactorial, chronic diseases involving neurodegeneration. According to recent studies, it is hypothesized that the intraneuronal and postsynaptic accumulation of misfolded proteins such as α-synuclein (α-syn) and tau, responsible for Lewy bodies (LB) and tangles, respectively, disrupts neuron functions. Considering the co-occurrence of α-syn and tau inclusions in the brains of patients afflicted with subtypes of dementia and LB disorders, the discovery and development of small molecules for the inhibition of α-syn and tau aggregation can be a potentially effective strategy to delay neurodegeneration. Urea is a chaotropic agent that alters protein solubilization and hydrophobic interactions and inhibits protein aggregation and precipitation. The presence of three hetero atoms (O/S and N) in proximity can coordinate with neutral, mono, or dianionic groups to form stable complexes in the biological system. Therefore, in this study, we evaluated urea and thiourea linkers with various substitutions on either side of the carbamide or thiocarbamide functionality to compare the aggregation inhibition of α-syn and tau. A thioflavin-T (ThT) fluorescence assay was used to evaluate the level of fibril formation and monitor the anti-aggregation effect of the different compounds. We opted for transmission electron microscopy (TEM) as a direct means to confirm the anti-fibrillar effect. The oligomer formation was monitored via the photoinduced cross-linking of unmodified proteins (PICUP). The anti-inclusion and anti-seeding activities of the best compounds were evaluated using M17D intracellular inclusion and biosensor cell-based assays, respectively. Disaggregation experiments were performed with amyloid plaques extracted from AD brains. The analogues with indole, benzothiazole, or <i>N</i>,<i>N</i>-dimethylphenyl on one side with halo-substituted aromatic moieties had shown less than 15% cutoff fluorescence obtained with the ThT assay. Our lead molecules <b>6T</b> and <b>14T</b> reduced α-syn oligomerization dose-dependently based on the PICUP assays but failed at inhibiting tau oligomer formation. The anti-inclusion effect of our lead compounds was confirmed using the M17D neuroblastoma cell model. Compounds <b>6T</b> and <b>14T</b> exhibited an anti-seeding effect on tau using biosensor cells. In contrast to the control, disaggregation experiments showed fewer Aβ plaques with our lead molecules (compounds <b>6T</b> and <b>14T</b>). Pharmacokinetics (PK) mice studies demonstrated that these two thiourea-based small molecules have the potential to cross the blood-brain barrier in rodents. Urea and thiourea linkers could be further improved for their PK parameters and studied for the anti-inclusion, anti-seeding, and disaggregation effects using transgenic mice models of neurodegenerative diseases.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453212","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}

{"title":"Novel Piperazine Based Compounds Target Alzheimer's Disease Relevant Amyloid β42 and Tau Derived Peptide AcPHF6, and the Lead Molecule Increases Viability in the Flies Expressing Human Tau Protein.","authors":"Christopher Armstrong, Dan Luo, Anna Gretzinger, Deepti Pandey, Andrew Lipchik, Sokol V Todi, Aloke K Dutta","doi":"10.1021/acschemneuro.4c00220","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00220","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the leading form of dementia in the United States and the world. The pathophysiology of AD is complex and multifaceted. Accumulation of senile plaques and neurofibrillary tangles (NFTs) are hallmarks of AD. The aggregation of amyloid β (senile plaques) and tau tangles (NFTs) results in the death of neurons in the cortex and hippocampus, which manifests itself in cognitive decline and memory loss. Current therapies rely on conventional approaches that have only treated the underlying symptoms without disease modification. Data from clinical studies point to a complex role of amyloid β (Aβ) in a way that enhances the tau phenotype throughout the disease process. To address the co-pathogenic role of Aβ and tau, we undertook development of multitarget compounds aiming at both tau and Aβ to slow or stop disease progression and provide neuroprotection. Here, we demonstrate a dose-dependent effect of the novel test compounds that inhibit aggregation of AcPHF6 (a shorter version of tau protein) and Aβ_1-42 peptides in thioflavin T fluorescent assays. The compounds were also shown to disaggregate preformed aggregates dose dependently. To further validate these findings, circular dichroism experiments were carried out to examine the nature of inhibition. Additionally, transmission electron microscopy experiments were carried out to gain insights into the morphologies of aggregates obtained from dose-dependent inhibition of AcPHF6 and Aβ_1-42 as well as dissociation of preformed aggregates from these peptides. Compounds <b>D-687</b> and <b>D-688</b> reversed Aβ_1-42 induced toxicity in SH-SH5Y cells, significantly demonstrating neuroprotective properties. Finally, in a study with <i>Drosophila melanogaster</i> expressing human tau protein isoform (2N4R) in all the neurons, compound <b>D-688</b> significantly increased the survival of flies compared to vehicle treated controls. Future studies will further examine the neuroprotective properties of these lead compounds in various animal models.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580909","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}

{"title":"Propionate Decreases Microglial Activation but Impairs Phagocytic Capacity in Response to Aggregated Fibrillar Amyloid Beta Protein.","authors":"Andrew Gold, Sarah Kaye, Jie Gao, Jiangjiang Zhu","doi":"10.1021/acschemneuro.4c00370","DOIUrl":"10.1021/acschemneuro.4c00370","url":null,"abstract":"<p><p>Microglia, the innate immune cell of the brain, are a principal player in Alzheimer's disease (AD) pathogenesis. Their surveillance of the brain leads to interaction with the protein aggregates that drive AD pathogenesis, most notably Amyloid Beta (Aβ). Microglia attempt to clear and degrade Aβ using phagocytic machinery, spurring damaging neuroinflammation in the process. Thus, modulation of the microglial response to Aβ is crucial in mitigating AD pathophysiology. SCFAs, microbial byproducts of dietary fiber fermentation, are blood-brain barrier permeable molecules that have recently been shown to modulate microglial function. It is unclear whether propionate, one representative SCFA, has beneficial or detrimental effects on microglia in AD. Thus, we investigated its impact on microglial Aβ response in vitro. Using a multiomics approach, we characterized the transcriptomic, metabolomic, and lipidomic responses of immortalized murine microglia following 1 h of Aβ stimulation, as well as characterizing Aβ phagocytosis and secretion of reactive nitrogen species. Propionate blunted the early inflammatory response driven by Aβ, downregulating the expression of many Aβ-stimulated immune genes, including those regulating inflammation, the immune complement system, and chemotaxis. Further, it reduced the expression of <i>Apoe</i> and inflammation-promoting Aβ-binding scavenger receptors such as <i>Cd36</i> and <i>Msr1</i> in favor of inflammation-dampening <i>Lpl</i>, although this led to impaired phagocytosis. Finally, propionate shifted microglial metabolism, altering phospholipid composition and diverting arginine metabolism, resulting in decreased nitric oxide production. Altogether, our data demonstrate a modulatory role of propionate on microglia that may dampen immune activation in response to Aβ, although at the expense of phagocytic capacity.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142407414","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}

{"title":"Rational Search for Betaine/GABA Transporter 1 Inhibitors─<i>In Vitro</i> Evaluation of Selected Hit Compound.","authors":"Kamil Łątka, Stefanie Kickinger, Zuzanna Rzepka, Paula Zaręba, Gniewomir Latacz, Agata Siwek, Małgorzata Wolak, Dorota Stary, Monika Marcinkowska, Petrine Wellendorph, Dorota Wrześniok, Marek Bajda","doi":"10.1021/acschemneuro.4c00425","DOIUrl":"10.1021/acschemneuro.4c00425","url":null,"abstract":"<p><p>Inhibitory neurotransmission mediated by γ-aminobutyric acid (GABA) plays an important role in maintaining body homeostasis. Disturbances in GABA signaling are implicated in a multitude of neurologic and psychiatric conditions, including epilepsy, ischemia, anxiety, depression, insomnia, and mood disorders. Clinically relevant increases in GABA neurotransmitter level can be achieved by inhibition of its uptake into presynaptic neurons and surrounding glial cells, driven by GABA transporters (GAT1, BGT1, GAT2, and GAT3). Herein, we focused on the search for inhibitors of the BGT1 transporter which is understudied and for which the therapeutic potential of its inhibition is partly unknown. We applied multilevel virtual screening to identify compounds with inhibitory properties. Among selected hits, compound <b>9</b> was shown to be a preferential inhibitor of BGT1 (IC₅₀ 13.9 μM). The compound also revealed some inhibitory activity against GAT3 (4x lower) while showing no or low activity (IC₅₀ > 100 μM) toward GAT1 and GAT2, respectively. The predicted binding mode of compound <b>9</b> was confirmed by mutagenesis studies on E52A, E52Y, Q299L, and E52A+Q299L human BGT1 mutants. Subsequent evaluation showed that the selected hit displayed no affinity toward major GABA_A receptor subtypes. Moreover, it was nontoxic when tested on normal human astrocytes and even showed some neuroprotective activity in SH-SY5Y cells. Compound <b>9</b> is considered a promising candidate for further evaluation of the therapeutic potential of BGT1 transporter inhibition and the development of novel inhibitors.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453216","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}

{"title":"Alzheimer's Disease: Exploring the Landscape of Cognitive Decline.","authors":"Rumiana Tenchov, Janet M Sasso, Qiongqiong Angela Zhou","doi":"10.1021/acschemneuro.4c00339","DOIUrl":"10.1021/acschemneuro.4c00339","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. The pathology of AD is marked by the accumulation of amyloid beta plaques and tau protein tangles in the brain, along with neuroinflammation and synaptic dysfunction. Genetic factors, such as mutations in APP, PSEN1, and PSEN2 genes, as well as the APOE ε4 allele, contribute to increased risk of acquiring AD. Currently available treatments provide symptomatic relief but do not halt disease progression. Research efforts are focused on developing disease-modifying therapies that target the underlying pathological mechanisms of AD. Advances in identification and validation of reliable biomarkers for AD hold great promise for enhancing early diagnosis, monitoring disease progression, and assessing treatment response in clinical practice in effort to alleviate the burden of this devastating disease. In this paper, we analyze data from the CAS Content Collection to summarize the research progress in Alzheimer's disease. We examine the publication landscape in effort to provide insights into current knowledge advances and developments. We also review the most discussed and emerging concepts and assess the strategies to combat the disease. We explore the genetic risk factors, pharmacological targets, and comorbid diseases. Finally, we inspect clinical applications of products against AD with their development pipelines and efforts for drug repurposing. The objective of this review is to provide a broad overview of the evolving landscape of current knowledge regarding AD, to outline challenges, and to evaluate growth opportunities to further efforts in combating the disease.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142398649","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}

{"title":"Interactions of Polychlorinated Biphenyls and Their Metabolites with the Brain and Liver Transcriptome of Female Mice.","authors":"Amanda J Bullert, Hui Wang, Anthony E Valenzuela, Kari Neier, Rebecca J Wilson, Jessie R Badley, Janine M LaSalle, Xin Hu, Pamela J Lein, Hans-Joachim Lehmler","doi":"10.1021/acschemneuro.4c00367","DOIUrl":"10.1021/acschemneuro.4c00367","url":null,"abstract":"<p><p>Exposure to polychlorinated biphenyls (PCBs) is linked to neurotoxic effects. This study aims to close knowledge gaps regarding the specific modes of action of PCBs in female C57BL/6J mice (>6 weeks) orally exposed for 7 weeks to a human-relevant PCB mixture (MARBLES mix) at 0, 0.1, 1, and 6 mg/kg body weight/day. PCB and hydroxylated PCB (OH-PCBs) levels were quantified in the brain, liver, and serum; RNA sequencing was performed in the striatum, prefrontal cortex, and liver, and metabolomic analyses were performed in the striatum. Profiles of PCBs but not their hydroxylated metabolites were similar in all tissues. In the prefrontal cortex, PCB exposure activated the oxidative phosphorylation respiration pathways, while suppressing the axon guidance pathway. PCB exposure significantly changed the expression of genes associated with neurodevelopmental and neurodegenerative diseases in the striatum, impacting pathways like growth hormone synthesis and dendrite development. PCBs did not affect the striatal metabolome. In contrast to the liver, which showed activation of metabolic processes following PCB exposure and the induction of cytochrome P450 enzymes, the expression of xenobiotic processing genes was not altered by PCB exposure in either brain region. Network analysis revealed complex interactions between individual PCBs (e.g., PCB28 [2,4,4'-trichlorobiphenyl]) and their hydroxylated metabolites and specific differentially expressed genes (DEGs), underscoring the need to characterize the association between specific PCBs and DEGs. These findings enhance the understanding of PCB neurotoxic mechanisms and their potential implications for human health.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142407413","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}

{"title":"The Importance of Stereochemistry in 5-HT₇R Modulation─A Case Study of Hydantoin Derivatives.","authors":"Katarzyna Kucwaj-Brysz, Sebastian Baś, Ewa Żesławska, Sabina Podlewska, Magdalena Jastrzębska-Więsek, Anna Partyka, Wojciech Nitek, Grzegorz Satała, Anna Wesołowska, Jadwiga Handzlik","doi":"10.1021/acschemneuro.4c00152","DOIUrl":"10.1021/acschemneuro.4c00152","url":null,"abstract":"<p><p>Serotonin 5-HT₇ receptor (5-HT₇R), one of the most recently discovered members of the serotonergic system, has become a promising target in the search for central nervous system disorders. Despite the number of preclinical results, none of the selective 5-HT₇R agents has been approved; therefore, the clinical significance of this protein has not been confirmed yet. Recently, we described very promising, selective, and highly potent hydantoin-derived 5-HT₇R antagonists with confirmed antidepressant activity <i>in vivo</i> and a very good ADMET profile; however, they have been tested in behavioral studies as racemates. In this work, the synthesis of optically pure hydantoin-derived 5-HT₇R agents using cost-effective, classical methods has been presented for the first time. X-ray crystallographic analysis confirmed the absolute configuration on both stereogenic centers and allowed for the elucidation of the mechanism of introduction of epichlorohydrin into the hydantoin N3-position. The radioligand binding results showed a clear configuration preference for 5-HT₇R affinity. The molecular modeling results further indicated the key interaction responsible for lower affinity (with amino acid I3 × 29). Finally, the comparison of the antidepressant and anxiolytic effects of racemates versus stereoisomers suggests an influence of additional, apart from the action on 5HT₇R, factors responsible for the activity <i>in vivo</i>, which is worthy of deeper insight within further studies.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453217","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}

{"title":"Transcranial Alternating Current Stimulation: A Novel Neuromodulatory Treatment for Anxiety and Related Disorders.","authors":"Yahui Chen, Bicheng Gao, Yuqi You","doi":"10.1021/acschemneuro.4c00642","DOIUrl":"10.1021/acschemneuro.4c00642","url":null,"abstract":"<p><p>Given the high prevalence and socioeconomic burden of anxiety disorders, there is an urgent need for effective, fast-acting, cost-efficient treatment alternatives to traditional psychotherapy. Transcranial alternating current stimulation (tACS), a noninvasive brain stimulation technique that modulates endogenous brain oscillations via the application of sinusoidal currents to the scalp, emerges as a promising neuromodulatory treatment. We reviewed oscillatory neuropsychopathology in anxiety, examined current evidence of tACS interventions for anxiety and related disorders, and proposed novel simulation targets and protocols. We emphasize the need for rigorously designed clinical trials to systematically investigate the neuropsychological effects of different tACS protocols on diverse populations with pathological anxiety.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520297","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}

{"title":"Fluorescence Detection and Inhibition Mechanisms of DNTPH on Aβ42 Oligomers Characterized as Products in the Four Stages of Aggregation.","authors":"Mengke Jia, Ye Li, Chuanbo Wang, Xvzhi Gao, Yvning Guan, Hongqi Ai","doi":"10.1021/acschemneuro.4c00509","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00509","url":null,"abstract":"<p><p>Aβ42 aggregation was implicated in the pathogenesis of Alzheimer's disease (AD) without effective treatment available currently. Future efforts in clinical trials should instead focus on applying those antiamyloid treatment strategies to the preclinical stage and \"the earlier, the better\". How to identify and inhibit Aβ42 oligomers in the different stages of aggregation is therefore becoming the key to controlling primary aggregation and consequent AD development. Aggregation-induced emission probe DNTPH was demonstrated recently, enabling detection of amyloid at wavelengths up to 710 nm and exhibiting strong inhibitory effects on Aβ fibrosis at low dose. However, the detection and inhibition mechanisms of Aβ oligomers at various early stages of aggregation remain unknown. To this end, we built four different morphologies of Aβ42 pentamers characterized by products in monomeric aggregate (P_M), primary nucleation (P_P), secondary nucleation (P_S), and fibril stages (P_F) to explore the distinguishable ability and inhibition mechanisms of DNTPH with different concentrations upon binding. The results showcased that DNTPH does detect the four different Aβ42 oligomers with conspicuous fluorescence (λ_{P_M} = 657 nm, λ_{P_P} = 639 nm, λ_{P_S} = 630 nm, and λ_{P_F} = 648 nm) but fails to distinguish them, indicating that additional improvements are required further for the probe to achieve it. The inhibition mechanisms of DNTPH on the four Aβ42 aggregation are however of amazing differences. For P_M and P_P, aggregation was inhibited by altering the secondary structural composition, i.e., by decreasing the β-sheet and toxic turn (residues 22-23) probabilities, respectively. For P_S, inhibition was achieved by segregating and keeping the two disordered monomeric species (P_SM) away from the ordered secondary seed species (P_SF) and consequently blocking further growth of the P_SF seed. The inhibition mechanism for P_S is first probed and proposed so far, as far as we know, and the corresponding aggregation stage of P_S is the most important one among the four stages. The inhibition of P_F was triggered by distorting the fibril chains, disrupting the ordered fibril surface for the contact of monomers. In addition, the optimal inhibitory concentrations of DNTPH for P_M, P_P, and P_F were determined to be 1:3, while for P_S, it was 1:5. This outcome offers a novel perspective for designing drugs targeting Aβ42 oligomers at different aggregation stages.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566452","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}

{"title":"Rational Design, Synthesis, and Evaluation of Rofecoxib-Based Photosensitizers for the NIR Imaging and Photo-Oxidization of Aβ Aggregates.","authors":"Gulziba Anwar, Yingmei Cao, Wen-Jing Shi, Li Niu, Jin-Wu Yan","doi":"10.1021/acschemneuro.4c00496","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00496","url":null,"abstract":"<p><p>The photo-oxidation of amyloid-β (Aβ) protein catalyzed by Aβ-targeting photosensitizers shows high potential in treating Alzheimer's disease (AD). Herein, we report the first example of photosensitizers based on the rofecoxib scaffold, in which rational introduction of the electron-absorbing pyridinium/quinolinium moiety to the skeleton of rofecoxib could not only extend the absorption and emission wavelengths but also increase the efficiency of singlet oxygen (¹O₂) production. The emission wavelengths of <b>R-S-MP</b>, <b>R-S-MC</b>, and <b>R-S-MQ</b> are red-shifted to 860 nm, which might benefit the NIR imaging of Aβ aggregates with low photoscattering and autofluorescence. In addition, <b>R-S-MP</b> can identify Aβ plaques in brain sections of AD mice and detect abnormal viscosity environments, facilitating the pathological study of Alzheimer's disease. Most importantly, upon complexation with Aβ plaques, <b>R-S-MP</b> and <b>R-S-MC</b> could produce high singlet oxygen (¹O₂) under light irradiation, which can achieve the specific photo-oxidation of Aβ protein. Our optimized photosensitizers could change the conformation of β-rich Aβ protein and enhance its clearance through the lysosomal pathway, leading to the reduction of the Aβ-mediated neurotoxicity. All these excellent characteristics of our dual-functional photosensitizers for simultaneous imaging and photo-oxidation of Aβ aggregates suggest their promising prospects in pathological research in AD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566454","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}