Cells最新文献

{"title":"Use of Amplified Lewy Body Dementia Fibrils and Autoradiography to Characterize Binding of Radioligand Tg-1-90B to Alpha-Synuclein Fibrils in Postmortem Brain Tissue.","authors":"Jennifer Y O'Shea, Dhruva D Dhavale, Helen Hwang, Zachary Smith, Thomas J A Graham, Robert H Mach, Paul T Kotzbauer","doi":"10.3390/cells14181477","DOIUrl":"10.3390/cells14181477","url":null,"abstract":"<p><p>Parkinson's disease (PD) and Lewy Body Dementia (LBD) are defined by accumulation of alpha-synuclein (Asyn) fibrils within Lewy bodies (LBs) and Lewy neurites (LNs). The development of a Positron Emission Tomography (PET) tracer for quantifying Asyn fibrils would improve diagnostic accuracy and provide a biomarker for disease progression. We previously described radioligand [³H]Tg-1-90B, which binds to in vitro Asyn fibrils (PDB 2N0A) via interactions with residues Y39, S42 and K44. Here, we performed molecular docking studies with Tg1-90B and PD/LBD Asyn fibrils (PDB 8A9L), which predicts interactions with residues Y39 and K43 in a structurally distinct binding site. In radioligand binding assays, Tg-1-90B has moderate to high affinity (K_d 17.5 nM) for amplified LBD fibrils (PDB 8FPT), whose protofilament fold is highly similar to PD/LBD fibrils (PBD 8A9L). Autoradiography confirmed binding of [³H]Tg-1-90B to LBs in PD brain tissue. However, Tg-1-90B also binds to amyloid-beta fibrils in Alzheimer's disease (AD) tissue, indicating insufficient selectivity for Asyn fibrils. These results indicate that Tg-1-90B binds to Asyn fibrils in PD tissue but needs further structural optimization. Binding assays with amplified LBD fibrils and autoradiography with postmortem PD tissue can guide further development of Asyn fibril PET ligands for PD/LBD.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 18","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Next-Generation mRNA Vaccines in Melanoma: Advances in Delivery and Combination Strategies.","authors":"Stefano Zoroddu, Luigi Bagella","doi":"10.3390/cells14181476","DOIUrl":"10.3390/cells14181476","url":null,"abstract":"<p><p>Messenger RNA (mRNA) vaccines have redefined cancer immunotherapy, offering unparalleled flexibility to encode tumor-specific antigens and to be adapted to individual mutational landscapes. Melanoma, with its high mutational burden and responsiveness to immune checkpoint blockade, has become the leading model for translating these advances into clinical benefit. Recent innovations in delivery-ranging from lipid nanoparticles and polymeric carriers to biomimetic hybrids and intratumoral administration-are dismantling long-standing barriers of stability, targeting, and immunogenicity. Clinical milestones, including the randomized phase IIb KEYNOTE-942, show that adding the personalized neoantigen vaccine mRNA-4157 (V940) to pembrolizumab prolonged recurrence-free survival versus pembrolizumab alone (HR 0.561, 95% CI 0.309-1.017; 18-month RFS 79% vs. 62%), with the ASCO 3-year update reporting 2.5-year RFS 74.8% vs. 55.6% and sustained distant metastasis-free survival benefit in resected high-risk melanoma. Parallel preclinical studies highlight the potential of multifunctional platforms co-delivering cytokines or innate agonists to reshape the tumor microenvironment and achieve durable systemic immunity. As artificial intelligence drives epitope selection and modular manufacturing accelerates personalization, mRNA vaccines may have the potential to transition from adjuncts to main therapies in melanoma and beyond.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 18","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PCSK9 Regulation of Lipid Metabolism in the Nervous System: Implications for Schwann Cell Function and Peripheral Neuropathy.","authors":"Agnieszka Nowacka, Maciej Śniegocki, Ewa A Ziółkowska","doi":"10.3390/cells14181479","DOIUrl":"10.3390/cells14181479","url":null,"abstract":"<p><p>Neural function relies on tightly regulated lipid metabolism to sustain membrane integrity, synaptic signaling, and energy production. Myelinating glia, particularly Schwann cells, require continuous lipid flux to build and maintain myelin, rendering them vulnerable to imbalances between lipid entry and oxidative capacity. Proprotein convertase subtilisin/kexin type 9 (PCSK9), widely studied in hepatic cholesterol regulation, has emerging roles in the nervous system. In the central nervous system (CNS), local PCSK9 expression influences low-density lipoprotein receptor (LDLR) family abundance, neuronal survival pathways, and neuroinflammatory tone, although circulating PCSK9 has limited parenchymal access due to the blood-brain barrier (BBB). In the peripheral nervous system (PNS), recent evidence highlights a PCSK9-CD36 axis in Schwann cells; genetic Pcsk9 loss elevates CD36, increases fatty-acid influx, promotes lipid droplet expansion and acylcarnitine accumulation, and triggers mitochondrial stress that manifests as hypomyelination, C-fiber pathology, and selective small-fiber neuropathy. These findings suggest that PCSK9 normally restrains CD36-dependent transport to align lipid supply with metabolic demand. Clinically, PCSK9 inhibitors have demonstrated cardiovascular benefit without major neurocognitive signals, yet small-fiber outcomes have not been systematically assessed. This review integrates current evidence on PCSK9 biology across neural compartments, highlights mechanistic links to Schwann cell lipid handling, and outlines research priorities to resolve neural safety and therapeutic potential in lipid-driven neuropathies.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 18","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Oral Peritumoral Tissue on Infiltration and Differentiation of Tumor-Associated Macrophages in Oral Squamous Cell Carcinoma.","authors":"Tianyan Piao, Kiyofumi Takabatake, Takuma Arashima, Yulu Zhao, Hotaka Kawai, Htoo Shwe Eain, Yamin Soe, Zin Zin Min, Keisuke Nakano, Hitoshi Nagatsuka","doi":"10.3390/cells14181481","DOIUrl":"10.3390/cells14181481","url":null,"abstract":"<p><p>The recruitment of tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) of oral squamous carcinoma (OSCC) affects significant cancer invasion; however, in the normal host tissue that is located in the cancer's surrounding area, this is poorly investigated. In this study, we examined the impact of gingival connective tissue cells (GCTCs) and periodontal ligament cells (PDLCs), which are involved in the invasive pathway of OSCC, on oral cancer invasion via TAMs recruitment. Transwell (migration) assays were used to examine the effects of GCTCs and PDLCs on the migration of macrophages, which indicated that the interaction between GCTCs and HSC-2/HSC-3 (human oral squamous cell carcinoma cell line) promoted the recruitment of macrophages, whereas the interaction between PDLCs was inhibited. An indirect co-culture was then used to examine the effects of GCTCs and PDLCs on the differentiation of macrophages, which indicated that the interaction between GCTCs enhanced their ability to transform into M2-type macrophages. Furthermore, the effects of GCTCs and PDLCs on the recruitment of CD45(+) monocytes, F4/80(+) M0 macrophages, iNOS(+) M1 macrophages, and CD163(+) M2 TAMs were assayed by immunohistochemistry. The results revealed that the interaction between GCTCs and HSC-2/HSC-3 promoted the infiltration of CD45(+) monocytes, F4/80(+) M0 macrophages, and CD163(+) M2 TAMs, whereas the PDLCs inhibited it, while their effect on iNOS(+) M1 macrophages was limited. Collectively, the GCTCs contributed to the infiltration of TAMs into the TME of OSCC cells, whereas the PDLCs exerted an inhibitory effect. These findings suggest a potential regulatory mechanism underlying the progression of OSCC.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 18","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lumpy Skin Disease Virus ORF137 Protein Inhibits Type I Interferon Production by Interacting with and Decreasing the Phosphorylation of IRF3.","authors":"Qunhua Ke, Kaishen Yao, Min Qu, Zhengji Liang, Miaomiao Li, Xiangwei Wang, Xiangping Yin, Yuefeng Sun","doi":"10.3390/cells14181475","DOIUrl":"10.3390/cells14181475","url":null,"abstract":"<p><p>Lumpy skin disease (LSD) is an invasive infectious disease caused by the lumpy skin disease virus (LSDV), which is detrimental to the production of cattle. LSDV encodes about 156 proteins, most of whose functions are still unknown. In this study, we found that the ORF137 protein was identified as one of the strongest inhibitors of IFN-β and ISG expression, determining LSDV ORF137 as a negative regulator of interferon (IFN) β signaling. Further evidence suggests that ORF137 interacts with the signal transduction factor IRF3 and inhibits the activation of IFN-β signaling by reducing Phospho-IRF3 (p-IRF3). Further investigation indicated that overexpression of ORF137 in BMEC could significantly inhibit the transcription of IFN-β and ISGs, thereby promoting the replication of LSDV. More importantly, through homologous recombination, we deleted the ORF137 gene from the LSDV/FJ/CHA/2021 strain and constructed the recombinant strain LSDV-ΔORF137-EGFP. Compared with the parental strain, LSDV-ΔORF137-EGFP showed a weakened effect on inhibiting the transcription of IFN-β and ISGs and a reduced replication level in infected MDBK cells. In summary, ORF137 facilitates LSDV replication by targeting IRF3 to inhibit IFN-β signaling. Our findings reveal a new mechanism by which LSDV suppresses the host antiviral response, which may facilitate the development of attenuated live vaccines for LSDV.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 18","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the CXCR4/CXCL12 Axis to Overcome Drug Resistance in Triple-Negative Breast Cancer.","authors":"Desh Deepak Singh, Dharmendra Kumar Yadav, Dongyun Shin","doi":"10.3390/cells14181482","DOIUrl":"10.3390/cells14181482","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) remains one of the most aggressive and treatment-resistant forms. TNBC is an aggressive and therapeutically resistant subtype of breast cancer, marked by the absence of estrogen, progesterone, and HER2 receptors. The lack of defined molecular targets significantly limits treatment options and contributes to high recurrence rates. Among the key pathways involved in TNBC progression and resistance, the CXCR4/CXCL12 chemokine axis has emerged as a critical player. CXCR4, a G-protein-coupled receptor, binds specifically to its ligand CXCL12, promoting tumour cell proliferation, metastasis, immune evasion, and stromal remodelling. Its overexpression is frequently associated with poor prognosis, disease progression, and resistance to conventional therapies in TNBC. This review explores how the chemokine receptor type 4 (CXCR4/CXCL12) axis facilitates drug resistance through mechanisms such as epithelial-mesenchymal transition (EMT), cancer stemness, and microenvironmental interactions. Notably, CXCR4 antagonists like plerixafor, balixafortide, and POL5551 have shown encouraging preclinical and clinical results, particularly when combined with chemotherapy or immunotherapy. Additionally, innovative strategies, including radiopharmaceuticals, peptide inhibitors, and nanotechnology-based delivery platforms, offer expanded therapeutic avenues. Despite persistent challenges such as tumour heterogeneity and potential toxicity, growing clinical evidence supports the translational relevance of this axis. This manuscript provides an in-depth analysis of CXCR4/CXCL12-mediated drug resistance in TNBC and evaluates current and emerging therapeutic interventions.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 18","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ashwagandha Root Extract Mitigates Fibromyalgia-like Symptoms via Neurochemical and Histological Modulation in Mice.","authors":"Razan Fawaz Hasanyn, Ashwaq H Batawi, Mona A Al-Thepyani, Reham Tash, Asma Almuhammadi, Ashwaq Hassan Alsabban, Badrah S Alghamdi","doi":"10.3390/cells14181478","DOIUrl":"10.3390/cells14181478","url":null,"abstract":"<p><p>Fibromyalgia syndrome (FMS) is a chronic disorder marked by widespread musculoskeletal pain, fatigue, mood disturbances, and cognitive impairments. Current treatments primarily focus on symptom management. Ashwagandha (<i>Withania somnifera</i>), a traditional Ayurvedic herb, is known for its adaptogenic and neuroprotective properties. This study evaluated the protective effects of the methanolic root extract of Ashwagandha (ARE) in a reserpine-induced fibromyalgia model in male Swiss albino mice. Mice received oral ARE (100 mg/kg) for 17 days and reserpine (0.5 mg/kg, subcutaneously) for three consecutive days to induce fibromyalgia-like symptoms. Behavioral assessments included Von Frey, tail suspension, rotarod, and Y-maze tests. Histological analysis was conducted on the hippocampus and thalamus; however, neurochemical analysis focused on markers such as serotonin, norepinephrine, IL-1β, TNFα, MDA, and NO. Results indicated that ARE significantly reduced pain and depressive-like behavior and improved motor function (<i>p</i> < 0.0001); however, no significant changes were observed in open-field locomotion. Histological examination revealed protection of Ashwagandha against neurodegeneration and improved hippocampal integrity, accompanied by increased serotonin and norepinephrine levels and decreased pro-inflammatory cytokines. These findings suggest that Ashwagandha root extract may offer therapeutic benefits for managing fibromyalgia symptoms.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 18","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural Simplification from Tricyclic to Bicyclic Scaffolds: A Long-Term Investigation in the Field of Adenosine Receptor Antagonists.","authors":"Costanza Ceni, Sara Calenda, Giulia Vagnoni, Daniela Catarzi, Flavia Varano, Vittoria Colotta","doi":"10.3390/cells14181480","DOIUrl":"10.3390/cells14181480","url":null,"abstract":"<p><p>Adenosine receptor (AR) antagonists have attracted considerable interest due to their therapeutic potential in a wide range of pathological conditions, including neurological, cardiovascular, and inflammatory disorders. Although a large number of AR antagonists have been developed worldwide, the interest in new derivatives remains high, and achieving subtype selectivity continue to be a major challenge. This review summarizes our research on adenosine receptor antagonists, highlighting the discovery of potent and selective compounds for the diverse AR subtypes across various chemical classes. Specifically, the paper focuses on the study of the triazolo[4,3-a]quinoxalin-1-one (<b>TQX</b>) and pyrazolo[3,4-c]quinoline (<b>PQ</b>) series, along with their simplified analogues, which have yielded highly potent and selective AR antagonists. An overview of the structure-activity relationship (SAR) studies and molecular docking investigations is provided, emphasizing the structural requirements for A_2A and A₃ receptor-ligand interaction. In addition, we present pharmacological studies of selected AR antagonists, in various in vitro and in vivo models of pain, depression, neuroinflammation-related diseases, and cancer.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 18","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pericyte Expression of VEGF-A Minimally Impacts Ocular Vascular Development and Neovascularization.","authors":"Yong-Seok Song, Shoujian Wang, Samay Inampudi, Hope Risa, Christine M Sorenson, Nader Sheibani","doi":"10.3390/cells14181473","DOIUrl":"10.3390/cells14181473","url":null,"abstract":"<p><p>Pericytes produce vascular endothelial growth factor-A (VEGF-A; hereafter referred to as VEGF). VEGF inhibits pericyte proliferation and migration through enhanced VEGFR2 and PDGFRβ heterodimerization. Heterodimerization of these receptors on perivascular supporting cells, mediated by VEGF in culture, mitigates signaling through these receptors and promotes a quiescent phenotype. However, the detailed cellular mechanisms and the significance of these interactions in vivo require further investigation. The cell-autonomous activities of pericyte VEGF expression during vascular development and neovascularization remain unknown. Here we utilized mice conditionally lacking <i>Vegfa</i> in pericytes (<i>Vegfa</i>^PC) to examine its impact on retinal vascular development and pathological ocular neovascularization. Vascular integrity was also assessed in older mice using fundus imaging and fluorescein angiography. The lack of <i>Vegfa</i> pericyte expression delayed the initial spreading of the superficial layer of the retinal vasculature. Mice lacking <i>Vegfa</i> pericyte expression had similar numbers of retinal endothelial cells and arteries to their wild-type littermates. However, the number of pericytes was significantly reduced in younger <i>Vegfa</i>^PC mice but increased in more mature mice. In addition, pericyte <i>Vegfa</i> deficiency did not impact responses during oxygen-induced ischemic retinopathy and laser-induced choroidal neovascularization. Thus, pericyte VEGF expression plays a role during early stages of retinal vascular development with limited influence on mature retinal vascularization, its integrity, and neovascularization.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 18","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12469127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PF-04691502, a PI3K/mTOR Dual Inhibitor, Ameliorates AD-like Pathology in a Mouse Model of AD.","authors":"Marika Lanza, Rossella Basilotta, Antonella Caccamo, Giovanna Casili, Alberto Repici, Salvatore Oddo, Emanuela Esposito","doi":"10.3390/cells14181474","DOIUrl":"10.3390/cells14181474","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disorder that significantly impacts the lives of patients and their families. The pathological features of AD include the accumulation of amyloid-β (Aβ) and Tau, which disrupt neuronal function and communication, ultimately leading to neuronal loss and brain atrophy. Efforts to understand the molecular mechanisms underlying these pathological changes have led to advancements in diagnostic techniques and potential therapeutic interventions. However, the complexity of AD necessitates further research to develop more effective treatments and, ideally, preventive measures. Extensive research suggests that diminishing mTOR signaling increases lifespan and health span across various species. Increased PI3K/mTOR signaling has been linked to the progression of AD pathology, leading to neuronal degeneration and impairments in cognitive function. In this study, we explored the therapeutic potential of PF-04691502, a dual PI3K/mTOR inhibitor, in Alzheimer's disease (AD)-like pathology using male and female B6.Cg-Tg(APPswe, PSEN1dE9)85Dbo/Mmjax mice (APP/PS1), a well-established transgenic model of AD. Eighteen-month-old APP/PS1 and wild-type mice received oral administration of PF-04691502 at a dose of 1 mg/kg for 12 weeks. Following the treatment period, spatial learning and memory were evaluated using the Morris water maze. Subsequently, the mice brains were collected for neuropathological and biochemical assessments. Our findings showed that PF-04691502 enhanced cognitive performance in APP/PS1 mice and significantly reduced insoluble Aβ accumulation in the brain. Mechanistically, these effects were associated with enhanced autophagy induction. Treatment with PF-04691502 increased the LC3-II/LC3-I ratio, upregulated Beclin-1, and elevated LAMP-2 levels, indicative of stimulated autophagosome formation and lysosomal activity. Overall, these preclinical results suggest that PF-04691502 holds promise as a potential therapeutic agent for AD and other aging-related neurodegenerative diseases involving mTOR pathway dysregulation.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 18","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}