ACS Chemical Neuroscience最新文献

{"title":"Quinazolinone-Hydrazine Cyanoacetamide Hybrids as Potent Multitarget-Directed Druggable Therapeutics against Alzheimer's Disease: Design, Synthesis, and Biochemical, In Silico, and Mechanistic Analyses.","authors":"Kandrakonda Yelamanda Rao, Remya Chandran, K V Dileep, Sri Charitha Gorantla, Shaik Jeelan Basha, Sreelakshmi Mothukuru, Irla Siva Kumar, Katta Vamsi, Sandeep Kumar, Aramati Bindu Madhava Reddy, Rajagopal Subramanyam, Amooru Gangaiah Damu","doi":"10.1021/acschemneuro.4c00424","DOIUrl":"10.1021/acschemneuro.4c00424","url":null,"abstract":"<p><p>The discovery of effective multitarget-directed ligands (MTDLs) against multifactorial Alzheimer's disease (AD) remnants has been focused in an incessant drug discovery pursuit. In this perception, the current study explores the rational design, synthesis, and evaluation of 26 quinazolinone-hydrazine cyanoacetamide hybrids <b>7(a-j)</b>, <b>8(a-j)</b>, and <b>9(a-f)</b> as MTDLs against AD. These new compounds were synthesized in four-step processes using simple phthalimide as the starting material without any major workup procedures and were characterized by different spectroscopic techniques. In Ellman's assay, the most potent analogues <b>7i</b>, <b>8j</b>, and <b>9d</b> were identified as selective and mixed-type inhibitors of hAChE. Furthermore, biophysical and computational assessments revealed that the analogues <b>7i</b>, <b>8j</b>, and <b>9d</b> were bound to both the catalytic active site and peripheral anionic site of hAChE with high affinity. The molecular dynamics simulation analysis highlighted the conformational changes of hAChE upon binding of <b>7i</b>, <b>8j</b>, and <b>9d</b> and also the stability of resulting biomolecular systems all over 100 ns simulations. In addition to antioxidant activity, the most active congeners were found to protect substantially SK-N-SH cells from oxidative damage. Decisively, the most active analogues <b>7i</b>, <b>8j</b>, and <b>9d</b> were assessed as potent Aβ_1-42 fibril modulators and protective agents against Aβ_1-42-induced toxicity in SH-SY5Y cells. Additionally, glioblastoma C6 cell-based assays also demonstrated the use of the most active congeners <b>7i</b>, <b>8j</b>, and <b>9d</b> as protective agents against Aβ_1-42-induced toxicity. Overall, this multifunctional capacity of quinazolinone-hydrazine cyanoacetamide hybrids demonstrated the noteworthy potential of these hybrids to develop as effectual MTDLs against AD. However, further pharmacokinetics, toxicology, and behavioral studies are warranted.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131135","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":"Can Targeted Protein Degradation Technology Provide a Potential Breakthrough in the Development of Anti-AD Drugs?","authors":"Baichen Xiong, Zuoaoyun Song, Leyan Wang, Ao Zhang, Yu Zhou, Na Zheng, Yuqing Wei, Yao Chen, Haopeng Sun","doi":"10.1021/acschemneuro.4c00590","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00590","url":null,"abstract":"Recent advancements in Alzheimer’s disease (AD) research have led to the approval of lecanemab and donanemab, highlighting the effectiveness of amyloid-beta (Aβ) degradation as a treatment for AD. The prospect of small molecule Aβ degraders as a potential treatment, which utilizes emerging targeted protein degradation technology, is exciting, given their ability to address some of the limitations of current therapies and their promising future in AD treatment. Despite facing challenges, these degraders are poised to become a future treatment option, harnessing scientific breakthroughs for more targeted and effective AD therapy.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251237","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":"Single-Molecule Fingerprinting Reveals Different Growth Mechanisms in Seed Amplification Assays for Different Polymorphs of α-Synuclein Fibrils.","authors":"Derrick Lau, Yuan Tang, Vijaya Kenche, Thomas Copie, Daryan Kempe, Eve Jary, Noah J Graves, Maté Biro, Colin L Masters, Nicolas Dzamko, Yann Gambin, Emma Sierecki","doi":"10.1021/acschemneuro.4c00185","DOIUrl":"10.1021/acschemneuro.4c00185","url":null,"abstract":"<p><p>α-Synuclein (αSyn) aggregates, detected in the biofluids of patients with Parkinson's disease (PD), have the ability to catalyze their own aggregation, leading to an increase in the number and size of aggregates. This self-templated amplification is used by newly developed assays to diagnose Parkinson's disease and turns the presence of αSyn aggregates into a biomarker of the disease. It has become evident that αSyn can form fibrils with slightly different structures, called \"strains\" or polymorphs, but little is known about their differential reactivity in diagnostic assays. Here, we compared the properties of two well-described αSyn polymorphs. Using single-molecule techniques, we observed that one of the polymorphs had an increased tendency to undergo secondary nucleation and we showed that this could explain the differences in reactivity observed in <i>in vitro</i> seed amplification assay and cellular assays. Simulations and high-resolution microscopy suggest that a 100-fold difference in the apparent rate of growth can be generated by a surprisingly low number of secondary nucleation \"points\" (1 every 2000 monomers added by elongation). When both strains are present in the same seeded reaction, secondary nucleation displaces proportions dramatically and causes a single strain to dominate the reaction as the major end product.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142091267","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}

{"title":"Unraveling the Structure and Dynamics of Ac-PHF6-NH₂ Tau Segment Oligomers.","authors":"Iuliia Stroganova, Zenon Toprakcioglu, Hannah Willenberg, Tuomas P J Knowles, Anouk M Rijs","doi":"10.1021/acschemneuro.4c00404","DOIUrl":"10.1021/acschemneuro.4c00404","url":null,"abstract":"<p><p>The aggregation of the proteins tau and amyloid-β is a salient feature of Alzheimer's disease, the most common form of neurodegenerative disorders. Upon aggregation, proteins transition from their soluble, monomeric, and functional state into insoluble, fibrillar deposits through a complex process involving a variety of intermediate species of different morphologies, including monomers, toxic oligomers, and insoluble fibrils. To control and direct peptide aggregation, a complete characterization of all species present and an understanding of the molecular processes along the aggregation pathway are essential. However, this is extremely challenging due to the transient nature of oligomers and the complexity of the reaction networks. Therefore, we have employed a combined approach that allows us to probe the structure and kinetics of oligomeric species, following them over time as they form fibrillar structures. Targeting the tau protein peptide segment Ac-PHF6-NH₂, which is crucial for the aggregation of the full protein, soft nano-electrospray ionization combined with ion mobility mass spectrometry has been employed to study the kinetics of heparin-induced intact oligomer formation. The oligomers are identified and characterized using high-resolution ion mobility mass spectrometry, demonstrating that the addition of heparin does not alter the structure of the oligomeric species. The kinetics of fibril formation is monitored through a Thioflavin T fluorescence assay. Global fitting of the kinetic data indicates that secondary nucleation plays a key role in the aggregation of the Ac-PHF6-NH₂ tau segment, while the primary nucleation rate is greatly accelerated by heparin.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102100","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}

{"title":"A Small Molecule Impedes the Aβ1–42 Tetramer Neurotoxicity by Preserving Membrane Integrity: Microsecond Multiscale Simulations","authors":"Subramanian Boopathi, Ramón Garduño-Juárez","doi":"10.1021/acschemneuro.4c00383","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00383","url":null,"abstract":"Amyloid-β (Aβ_1–42) peptides aggregated into plaques deposited in the brain are the main hallmark of Alzheimer’s disease (AD), a social and economic burden worldwide. In this context, insoluble Aβ_1–42 fibrils are the main components of plaques. The recent trials that used approved AD drugs show that they can remove the fibrils from AD patients’ brains, but they did not halt the course of the disease. Mounting evidence envisages that the soluble Aβ_1–42 oligomers’ interactions with the neuronal membrane trigger higher cell death than Aβ_1–42 fibril interactions. Developing a compound that can alleviate the oligomer’s toxicity is one of the most demanding tasks for curing the disease. We performed two molecular dynamics (MD) simulations in an explicit solvent model. In the first case, 55-μs of multiscale all-atom (AA)/coarse-grained (CG) MD simulations were carried out to decipher the impact of a previously described small anti-Aβ molecule, termed M30 (2-octahydroisoquinolin-2(1H)-ylethanamine), on an Aβ_1–42 tetramer structure in close contact with a DMPC bilayer. In the second case, 15-μs AA/CG MD simulations were performed to rationalize the dynamics between Aβ_1–42 and Aβ_1–42-M30 tetramer complexes embedded in DMPC. On the membrane bilayer, we found that the Aβ_1–42 tetramer penetrates the bilayer surface due to unrestricted conformational flexibility and many contacts with the membrane phosphate groups. In contrast, no Aβ_1–42-M30 tetramer penetration was observed during the entire course of the simulation. In the case of the membrane-embedded Aβ_1–42 tetramer, the integrity of the bottom bilayer leaflet was severely affected by the interactions between the negatively charged phosphate groups and the positively charged residues of the Aβ_1–42 tetramer, resulting in a deep tetramer penetration into the bilayer hydrophobic region. These contacts were not observed in the case of the membrane-embedded Aβ_1–42-M30 tetramer. It was noted that M30 molecules bind to Aβ_1–42 tetramer through hydrogen bonds, resulting in a conformational stable Aβ_1–42-M30 complex. The associated complex has reduced conformational changes and an enhanced rigidity that prevents the tetramer dissociation by interfering with the tetramer-membrane contacts. Our findings suggest that the M30 molecules could bind to Aβ_1–42 tetramer resulting in a rigid structure, and that such complexes do not significantly perturb the membrane bilayer organization. These observations support the <i>in vitro</i> and <i>in vivo</i> experimental evidence that the M30 molecules prevent synaptotocity, improving AD-affected mice memory.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251235","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":"Pore Formation by Amyloid-like Peptides: Effects of the Nonpolar-Polar Sequence Pattern.","authors":"Warin Rangubpit, Siwaporn Sungted, Jirasak Wong-Ekkabut, Hannah E Distaffen, Bradley L Nilsson, Cristiano L Dias","doi":"10.1021/acschemneuro.4c00333","DOIUrl":"10.1021/acschemneuro.4c00333","url":null,"abstract":"<p><p>One of the mechanisms accounting for the toxicity of amyloid peptides in diseases like Alzheimer's and Parkinson's is the formation of pores on the plasma membrane of neurons. Here, we perform unbiased all-atom simulations of the full membrane damaging pathway, which includes adsorption, aggregation, and perforation of the lipid bilayer accounting for pore-like structures. Simulations are performed using four peptides made with the same amino acids. Differences in the nonpolar-polar sequence pattern of these peptides prompt them to adsorb into the membrane with the extended conformations oriented either parallel [peptide labeled F1, Ac-(FKFE)₂-NH₂], perpendicular (F4, Ac-FFFFKKEE-NH₂), or with an intermediate orientation (F2, Ac-FFKKFFEE-NH₂, and F3, Ac-FFFKFEKE-NH₂) in regard to the membrane surface. At the water-lipid interface, only F1 fully self-assembles into β-sheets, and F2 peptides partially fold into an α-helical structure. The β-sheets of F1 emerge as electrostatic interactions attract neighboring peptides to intermediate distances where nonpolar side chains can interact within the dry core of the bilayer. This complex interplay between electrostatic and nonpolar interactions is not observed for the other peptides. Although β-sheets of F1 peptides are mostly parallel to the membrane, some of their edges penetrate deep inside the bilayer, dragging water molecules with them. This precedes pore formation, which starts with the flow of two water layers through the membrane that expand into a stable cylindrical pore delimited by polar faces of β-sheets spanning both leaflets of the bilayer.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034419","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":"Kappa Opioid Receptor Activation Induces Epigenetic Silencing of Brain-Derived Neurotropic Factor <i>via</i> HDAC5 in Depression.","authors":"Anubhav Yadav, Shalini Dogra, Arun Kumar Boda, Poonam Kumari, Ajeet Kumar, Manish K Dash, Prem N Yadav","doi":"10.1021/acschemneuro.4c00175","DOIUrl":"10.1021/acschemneuro.4c00175","url":null,"abstract":"<p><p>Treatment-resistant depression (TRD) occurs in almost 50% of the depressed patients. Central kappa opioid receptor (KOR) agonism has been demonstrated to induce depression and anxiety, while KOR antagonism alleviates depression-like symptoms in rodent models and TRD in clinical studies. Previously, we have shown that sustained KOR activation leads to a TRD-like phenotype in mice, and modulation of brain-derived neurotrophic factor (BDNF) expression in the prefrontal cortex (PFC) appears to be one of the molecular determinants of the antidepressant response. In the present study, we observed that sustained KOR activation by a selective agonist, U50488, selectively reduced the levels of <i>Bdnf</i> transcripts <i>II</i>, <i>IV</i>, and <i>Bdnf</i> CDS (protein-coding Exon IX) in the PFC and cultured primary cortical neurons, which was blocked by selective KOR antagonist, <i>norbinaltorphimine</i>. Considering the crucial role of epigenetic pathways in BDNF expression, we further investigated the role of various epigenetic markers in KOR-induced BDNF downregulation in mice. We observed that treatment with U50488 resulted in selective and specific downregulation of acetylation at the ninth lysine residue of the histone H3 protein (H3K9ac) and upregulation of histone deacetylase 5 (HDAC5) expression in the PFC. Further, using anti-H3K9ac and anti-HDAC5 antibodies in the chromatin immune precipitation assay, we detected decreased enrichment of H3K9ac and increased HDAC5 binding at <i>Bdnf</i> II and IV transcripts after U50488 treatment, which were blocked by a selective KOR antagonist, <i>norbinaltorphimine</i>. Further mechanistic studies using HDAC5 selective inhibitor, LMK235, in primary cortical neurons and adeno-associated viral shRNA-mediated HDAC5-knockdown in the PFC of mice demonstrated an essential role of HDAC5 in KOR-mediated reduction of <i>Bdnf</i> expression <i>in</i> the PFC and in depression-like symptoms in mice. These results suggest that KOR engages multiple pathways to induce depression-like symptoms in mice and provide novel insights into the mechanisms by which activation of KOR regulates major depressive disorders.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078327","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":"Discovery of VU6007496: Challenges in the Development of an M₁ Positive Allosteric Modulator Backup Candidate.","authors":"Julie L Engers, Katrina A Bollinger, Rory A Capstick, Madeline F Long, Aaron M Bender, Jonathan W Dickerson, Weimin Peng, Christopher C Presley, Hyekyung P Cho, Alice L Rodriguez, Colleen M Niswender, Sean P Moran, Zixiu Xiang, Anna L Blobaum, Olivier Boutaud, Jerri M Rook, Darren W Engers, P Jeffrey Conn, Craig W Lindsley","doi":"10.1021/acschemneuro.4c00508","DOIUrl":"10.1021/acschemneuro.4c00508","url":null,"abstract":"<p><p>Herein we report progress toward a backup clinical candidate to the M₁ positive allosteric modulator (PAM) VU319/ACP-319. Scaffold-hopping from the pyrrolo[2,3-<i>b</i>]pyridine-based M₁ PAM VU6007477 to isomeric pyrrolo[3,2-<i>b</i>]pyridine and thieno[3,2-<i>b</i>]pyridine congeners identified several backup contenders. Ultimately, VU6007496, a pyrrolo[3,2-<i>b</i>]pyridine, advanced into late stage profiling, only to be plagued with unanticipated, species-specific metabolism and active/toxic metabolites which were identified in our phenotypic seizure liability <i>in vivo</i> screen, preventing further development. However, VU6007496 proved to be a highly selective and CNS penetrant M₁ PAM, with minimal agonism, that displayed excellent multispecies IV/PO pharmacokinetics (PK), CNS penetration, no induction of long-term depression (or cholinergic toxicity) and robust efficacy in novel object recognition (minimum effective dose = 3 mg/kg p.o.). Thus, VU6007496 can serve as another valuable <i>in vivo</i> tool compound in rats and nonhuman primates, but not mouse, to study selective M₁ activation.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085834","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}

{"title":"Low-Dose Radiation Induces Alterations in Fatty Acid and Tyrosine Metabolism in the Mouse Hippocampus: Insights from Integrated Multiomics.","authors":"Rekha Koravadi Narasimhamurthy, Babu Santhi Venkidesh, Sampara Vasishta, Manjunath B Joshi, Bola Sadashiva Satish Rao, Krishna Sharan, Kamalesh Dattaram Mumbrekar","doi":"10.1021/acschemneuro.4c00231","DOIUrl":"10.1021/acschemneuro.4c00231","url":null,"abstract":"<p><p>In recent years, there has been a drastic surge in neurological disorders with sporadic cases contributing more than ever to their cause. Radiation exposure through diagnostic or therapeutic routes often results in neurological injuries that may lead to neurodegenerative pathogenesis. However, the underlying mechanisms regulating the neurological impact of exposure to near-low doses of ionizing radiation are not known. In particular, the neurological changes caused by metabolomic reprogramming have not yet been elucidated. Hence, in the present study, C57BL/6 mice were exposed to a single whole-body X-ray dose of 0.5 Gy, and 14 days post-treatment, the hippocampus was subjected to metabolomic analysis. The hippocampus of the irradiated animals showed significant alterations in 15 metabolites, which aligned with altered tyrosine, phenylalanine, and alpha-linolenic acid metabolism and the biosynthesis of unsaturated fatty acids. Furthermore, a multiomics interaction network comprising metabolomics and RNA sequencing data analysis provided insights into gene-metabolite interactions. Tyrosine metabolism was revealed to be the most altered, which was demonstrated by the interaction of several crucial genes and metabolites. The present study revealed the regulation of low-dose radiation-induced neurotoxicity at the metabolomic level and its implications for the pathogenesis of neurological disorders. The present study also provides novel insights into metabolomic pathways altered following near-low-dose IR exposure and its link with neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054176","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}

{"title":"EphA4 Targeting Peptide-Conjugated Extracellular Vesicles Rejuvenates Adult Neural Stem Cells and Exerts Therapeutic Benefits in Aging Rats","authors":"Satyajit Ghosh, Rajsekhar Roy, Nabanita Mukherjee, Surojit Ghosh, Moumita Jash, Aniket Jana, Surajit Ghosh","doi":"10.1021/acschemneuro.4c00331","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00331","url":null,"abstract":"Aging and various neurodegenerative diseases cause significant reduction in adult neurogenesis and simultaneous increase in quiescent neural stem cells (NSCs), which impact the brain’s regenerative capabilities. To deal with this challenging issue, current treatments involve stem cell transplants or prevention of neurodegeneration; however, the efficacy or success of this process remains limited. Therefore, extensive and focused investigation is highly demanding to overcome this challenging task. Here, we have designed an efficient peptide-based EphA4 receptor-targeted ligand through an in silico approach. Further, this strategy involves chemical conjugation of the peptide with adipose tissue stem cell-derived EV (Exo-pep-11). Interestingly, our newly designed engineered EV, Exo-pep-11, targets NSC through EphA4 receptors, which offers promising therapeutic advantages by stimulating NSC proliferation and subsequent differentiation. Our result demonstrates that NSC successfully internalized Exo-pep-11 in both in vitro culture conditions as well as in the in vivo aging rats. We found that the uptake of Exo-pep-11 decreased by ∼2.3-fold when NSC was treated with EphA4 antibody before Exo-pep-11 incubation, which confirms the receptor-specific uptake of Exo-pep-11. Exo-pep-11 treatment also increases NSC proliferation by ∼1.9-fold and also shows ∼1.6- and ∼2.4-fold increase in expressions of Nestin and ID1, respectively. Exo-pep-11 also has the potential to increase neurogenesis in aging rats, which is confirmed by ∼1.6- and ∼1.5-fold increases in expressions of TH and Tuj1, respectively, in rat olfactory bulb. Overall, our findings highlight the potential role of Exo-pep-11 for prospective applications in combating age-related declines in NSC activity and neurogenesis.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251238","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}