Molecular and Cellular Neuroscience最新文献

{"title":"Stress-induced neuroinflammation and synaptic dysregulation: Linking HPA axis to glutamate and NMDA receptors.","authors":"Akhil Sharma, Thakur Gurjeet Singh","doi":"10.1016/j.mcn.2026.104097","DOIUrl":"https://doi.org/10.1016/j.mcn.2026.104097","url":null,"abstract":"<p><p>Chronic stress is a major risk factor for psychiatric and neurological disorders, operating through interconnected molecular cascades that link neuroendocrine dysfunction to synaptic pathology. This review mechanistically examines how stress-induced hypothalamic-pituitary-adrenal (HPA) axis hyperactivation sustains glucocorticoid release, driving microglial activation and astrocytic reactivity toward pro-inflammatory phenotypes characterized by immunometabolic reprogramming. Key inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and quinolinic acid (QUIN) derived from the upregulated kynurenine pathway (KP)- impair glutamate homeostasis by compromising astrocytic reuptake and promoting excitotoxic extrasynaptic N-methyl-d-aspartate receptor (NMDAR) signaling. These pathological alterations disrupt synaptic plasticity through modified NMDAR subunit composition, impaired long-term potentiation (LTP), and complement cascade-mediated synaptic pruning, establishing a self-perpetuating cycle of vulnerability particularly within the hippocampus and prefrontal cortex. Consequently, by elucidating these interconnected pathways reveals promising therapeutic targets, including microglial phenotype modulators, NMDAR-specific interventions, and integrated pharmacological and non-pharmacological strategies aimed at restoring synaptic homeostasis and circuit function. Ultimately, this review maps these biological pathways to outline protective interventions against the physical damage of chronic stress, offering a roadmap for new treatments to restore healthy neural connections and brain function.</p>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":" ","pages":"104097"},"PeriodicalIF":2.4,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840170","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 effects of GLP-1 receptor agonists on Alzheimer's pathophysiology: A systematic review.","authors":"Eve Corcoran, Michael Kettlety, Urwa Mogul, Jennifer Ndiforngwah Azah, Simon C Cork","doi":"10.1016/j.mcn.2026.104091","DOIUrl":"https://doi.org/10.1016/j.mcn.2026.104091","url":null,"abstract":"<p><strong>Background: </strong>The incidence of Alzheimer's disease (AD) is increasing globally but there are limited effective therapies available. Recently, evidence has demonstrated a role of GLP-1 receptor (GLP-1R) agonists, commonly used in the treatment of type 2 diabetes, may have therapeutic potential in AD. GLP-1R agonists have exhibited their neuroprotective role by targeting tau hyperphosphorylation and the accumulation of beta-amyloid (Aβ) plaques. This systematic review aims to evaluate the effectiveness of liraglutide, semaglutide, exenatide and dulaglutide on AD pathology with a focus on the key biomarkers: hyperphosphorylated tau and Aβ.</p><p><strong>Methods: </strong>A systematic literature search was conducted using PubMed, Embase and Cochrane Library. Inclusion criteria involved pre-clinical and clinical studies investigating the effects of GLP-1 agonists dulaglutide, liraglutide, semaglutide or exenatide on Aβ and tau pathology. Randomised and non-randomised studies were included. Exclusion criteria involved studies evaluating GLP-1R agonists other than those specified.</p><p><strong>Results: </strong>This review examined thirty preclinical studies investigating the effects of four GLP-1 receptor agonists on Alzheimer's disease pathology, particularly Aβ plaque accumulation and tau hyperphosphorylation. Most studies focused on liraglutide, which consistently reduced both Aβ and tau pathology in animal and cell models. Dulaglutide, although studied less frequently, consistently reduced tau phosphorylation and Aβ accumulation in mouse models while also improving cognitive outcomes. Semaglutide also showed largely positive effects with four studies reporting reduced Aβ or tau pathology, though one study reported no benefit. Two clinical studies were also reviewed. A phase II trial of Exenatide showed reduced plasma Aβ42 in extracellular vesicles but not cognitive benefit. A smaller liraglutide trial demonstrated no reduction in Aβ burden or cognitive change though it preserved brain glucose metabolism. An EXSCEL trial showed significant changes in systemic inflammatory markers. While pre-clinical data has been encouraging, clinical evidence remains limited.</p><p><strong>Conclusions: </strong>There is consistent preclinical evidence that GLP-1R agonists are effective in reducing Aβ levels and hyperphosphorylated tau. While the neuroprotective effect in preclinical studies is clear, clinical findings have so far failed to demonstrate an arresting effect on cognitive.</p><p><strong>Registration: </strong>PROSPERO CRD420251029748.</p>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":" ","pages":"104091"},"PeriodicalIF":2.4,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776319","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":"4-MEC potentially triggers CAV1 via the BDNF-TrkB signaling pathway","authors":"Wangping Zhang ,&nbsp;Fangqi Cao ,&nbsp;Ming Li ,&nbsp;Zheyu Fan ,&nbsp;Liren Wu ,&nbsp;Wenbin Liu ,&nbsp;Ping Shi","doi":"10.1016/j.mcn.2026.104074","DOIUrl":"10.1016/j.mcn.2026.104074","url":null,"abstract":"<div><div>4-Methylethcathinone (4-MEC), a synthetic cathinone with psychostimulant properties, is increasingly abused as a “designer drug”. However, its molecular mechanisms, particularly those related to neuroplasticity regulation, remain poorly understood. Caveolin-1 (CAV1) is a scaffolding protein of membrane lipid rafts and has been confirmed to organize multiple synaptic signaling proteins to regulate synaptic signaling and neuroplasticity. Herein, we investigated whether CAV1 modulates 4-MEC-induced alterations in the BDNF-TrkB signal pathway and neuroplasticity markers in human SH-SY5Y neuroblastoma cells and a mouse-conditioned place preference (CPP) model. Using qRT-PCR and Western blotting, we demonstrated that 4-MEC significantly upregulated CAV1 mRNA and protein levels, as well as components of the BDNF-TrkB signaling pathway and neuroplasticity markers (GAP43, MAP2, SYP). siRNA-mediated CAV1 knockdown abolished 4-MEC-induced increases in these proteins and neuroplasticity-related mRNAs, whereas CAV1 overexpression potentiated these effects. Additionally, molecular docking predicted potential binding sites between 4-MEC and CAV1. Meanwhile, protein docking also predicted the potential binding sites between CAV1 and TrkB, and co-immunoprecipitation confirmed their physical interactions in SH-SY5Y cells. In the mice exposed to 4-MEC in the CPP paradigm, we observed similar upregulation of CAV1, BDNF-TrkB signaling pathway components, and neuroplasticity markers in the brain. These findings identify CAV1 as a potential critical mediator of 4-MEC's neuroadaptive effects through the BDNF-TrkB signal pathway to regulate neuroplasticity. It suggests a possible novel molecular target for synthetic cathinone toxicity, with potential implications for forensic research.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"136 ","pages":"Article 104074"},"PeriodicalIF":2.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146220456","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":"Modeling the functional impact of CPEB3 and CPEB4 dysregulation in autism: A theoretical–computational framework","authors":"Lenin González-Paz ,&nbsp;Alejandro Vivas ,&nbsp;Arlene Cardozo-Urdaneta ,&nbsp;Carla Lossada ,&nbsp;Anibal Mendez ,&nbsp;Ariana Delgado ,&nbsp;Yovani Marrero-Ponce ,&nbsp;Felix Martinez-Rios ,&nbsp;Yunierkis Pérez-Castillo ,&nbsp;Ysaías J. Alvarado","doi":"10.1016/j.mcn.2026.104072","DOIUrl":"10.1016/j.mcn.2026.104072","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) involves impaired synaptic plasticity tightly coupled to local mRNA translation. Cytoplasmic polyadenylation element-binding proteins 3 and 4 (CPEB3 and CPEB4) are post-transcriptional regulators of neuronal mRNA translation that may contribute to ASD-related molecular alterations. In this theoretical–computational study, we develop a weighted functional impact model that integrates transcriptomic expression with intrinsic molecular constraints of CPEB3 and CPEB4 to estimate regional and cell type–specific vulnerability in ASD. Coarse-grained molecular dynamics (MD) simulations were quantitatively analyzed to assess aggregation, diffusion, and cluster stability under cell type–specific cytoplasmic conditions, with statistical uncertainty explicitly evaluated. The anterior cingulate cortex and thalamus emerged as primary vulnerability sites. Despite higher CPEB4 expression—mainly in glial cells—our weighted functional impact model predicted greater theoretical susceptibility linked to CPEB3 dysfunction, particularly in inhibitory and excitatory neurons. MD simulations revealed that CPEB3 forms transient diffusion-permissive aggregates, whereas CPEB4 tends to assemble into more stable condensates. These complementary behaviors suggest differential but interdependent regulation of neuronal and glial functions. Importantly, the proposed framework provides experimentally testable predictions on how protein–protein interactions, microexon loss, and cytoplasmic crowding influence translational control in ASD. This integrative approach provides a quantitative and biologically grounded framework to investigate how post-transcriptional regulators contribute to ASD-relevant molecular vulnerability.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"136 ","pages":"Article 104072"},"PeriodicalIF":2.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046865","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":"Multi-level computational analysis identifies schizophrenia missense SNPs with implications for synaptic function, neuroimmune dysfunction, and antipsychotic response","authors":"Fatimah M. Coppin ,&nbsp;Michelle Kwon ,&nbsp;Ariya Bakhteri ,&nbsp;Aziza Abugaliyeva","doi":"10.1016/j.mcn.2026.104071","DOIUrl":"10.1016/j.mcn.2026.104071","url":null,"abstract":"<div><div>Schizophrenia (SCZ) has strong genetic underpinnings, yet the functional impact of associated genetic variants remains unclear. We computationally analyzed SCZ-associated missense single-nucleotide polymorphisms (SNPs) from the National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) Genome-Wide Association Studies (GWAS) Catalog to identify variants with significant functional consequences. From 5083 SCZ-associated SNPs, we prioritized five genes harboring highly deleterious missense SNPs: STX2, BTN2A1, and UGT1A8/9/10. We integrated pathogenicity predictions, protein stability assessments, structural analyses, and protein-protein interaction networks to understand how these SCZ-associated missense variants may contribute to disease pathogenesis. Amino acid changes, or variants, of the five genes were consistently predicted to decrease protein stability. The STX2 variant affects the syntaxin N-terminus domain, crucial for neurotransmitter release and implicated in antipsychotic pharmacology. The BTN2A1 variants disrupt immunoglobulin-like domains involved in T-cell regulation. The UGT1A8/9/10 variant impacts the UDP-glycosyltransferase domain, potentially altering drug metabolism. Protein interaction analyses revealed connections to synaptic signaling, immune regulation, and xenobiotic metabolism pathways implicated in SCZ. Our findings illuminate potential molecular mechanisms by which these genetic variants may contribute to SCZ pathophysiology and highlight promising targets for therapeutic development.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"136 ","pages":"Article 104071"},"PeriodicalIF":2.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989933","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":"Select NSAIDs enhance peripheral nerve growth and calcium signaling through PPARγ activation","authors":"Jarin Tusnim ,&nbsp;Sheetal Padhi ,&nbsp;Karl Chelala ,&nbsp;J. Patrick O'Connor ,&nbsp;Bryan J. Pfister ,&nbsp;Bonnie L. Firestein ,&nbsp;Jonathan M. Grasman","doi":"10.1016/j.mcn.2025.104067","DOIUrl":"10.1016/j.mcn.2025.104067","url":null,"abstract":"<div><div>Peripheral nerve injuries (PNIs) are a significant health concern, affecting millions of individuals and result in debilitating sensory and motor deficits, as well as severe neuropathic pain. Treatment of PNIs depend on severity and gap length, with small gaps repaired by sutures and larger ones requiring autologous nerve grafting, the gold standard for bridging defects. However, autologous grafting also has significant limitations, including low recovery rates and complications such as neuroma formation. Tissue engineering and regenerative medicine offer promising alternatives but lack effective treatments directly enhancing nerve regeneration. Our previous research explored the potential of repurposing non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen and indomethacin, to promote peripheral nerve regeneration (PNR). These drugs demonstrated enhanced axonal growth and calcium signaling, suggesting a dual role in promoting neuronal recovery. The present study aimed to identify the underlying mechanism of this drug-mediated axonal growth. We hypothesized that ibuprofen and indomethacin function as peroxisome proliferator-activated receptor gamma (PPARγ) agonists, inhibiting RhoA activation and thus facilitating axonal growth. To test this, we performed immunostaining, Western blotting, and calcium imaging on dorsal root ganglion (DRG) explants treated with these drugs, both with and without PPARγ antagonists. We also investigated whether cyclooxygenase (COX) inhibition, the primary pain-relieving mechanism of NSAIDs, contributes to axonal growth. Our findings indicate that ibuprofen and indomethacin promote axonal growth through PPARγ activation, independent of COX inhibition, suggesting that targeting the PPARγ pathway could be a novel therapeutic strategy for enhancing nerve regeneration and improving outcomes for patients with PNIs.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"136 ","pages":"Article 104067"},"PeriodicalIF":2.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775057","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":"Irisin regulates mitochondrial function to support synaptogenesis in the developing hippocampus","authors":"Mary R. Josten ,&nbsp;Kyra N. Parker ,&nbsp;Crystal Dillon ,&nbsp;Heiko Jansen ,&nbsp;Gary A. Wayman","doi":"10.1016/j.mcn.2026.104073","DOIUrl":"10.1016/j.mcn.2026.104073","url":null,"abstract":"<div><div>Hippocampal synapse proliferation is a critical period in brain development that demands vast supplies of chemical energy. Maternally derived hormones exert vital effects on mitochondrial function in the developing brain, thus determining neuronal synapse proliferative capacity. Here we investigated the mechanisms by which irisin, through the neuronal uncoupling proteins (UCPs) UCP2, UCP4, and UCP5, regulates mitochondrial function to facilitate the growth and maturation of dendritic spines in developing hippocampal neurons. Irisin treatment increased mitochondrial respiration and mitochondrial membrane potential, but not reactive oxygen species production in an in vitro model of developing hippocampal neurons. Irisin treatment also increased the expression of UCP2, UCP4, and UCP5<em>.</em> Knockdown of UCP2, UCP4, and UCP5 exerted differential effects on basal and irisin-stimulated phenotypes in cultured neurons, while overexpression of UCP2, UCP4, or UCP5 exerted differential effects on basal mitochondrial membrane potential, reactive oxygen species levels, and synaptogenesis. Together, these data suggest a role for irisin in regulating neuronal mitochondrial function through a UCP-dependent mechanism to support synaptogenesis during hippocampal development.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"136 ","pages":"Article 104073"},"PeriodicalIF":2.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146113441","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 extracellular domain of mGluR6 regulates targeting to the conventional secretion pathway","authors":"Andrew P. Rideout ,&nbsp;Omar W. Abuelatta ,&nbsp;Melina A. Agosto","doi":"10.1016/j.mcn.2025.104068","DOIUrl":"10.1016/j.mcn.2025.104068","url":null,"abstract":"<div><div>In the retina, rod and cone photoreceptors relay information to bipolar cells at glutamatergic synapses. At dendritic tips of ON-type bipolar cells, which depolarize in response to light, the metabotropic glutamate receptor mGluR6 is required for neurotransmitter detection. mGluR6 also has a critical interaction with the presynaptic cell adhesion molecule ELFN1, and N-linked glycosylation of mGluR6 is required for this interaction. In the retina and in heterologous cells, mGluR6 undergoes conventional secretory trafficking with complex glycosylation acquired in the Golgi. However, the mechanisms regulating mGluR6 secretory trafficking are poorly understood. Like other class C GPCRs, mGluR6 has a large extracellular domain, which includes a bi-lobed ligand binding domain. We show that a series of small deletions in the upper lobe of the ligand-binding domain led to exclusive use of unconventional secretion and plasma membrane insertion of immature core-glycosylated protein in heterologous cells. Deletion of larger regions partially restored Golgi trafficking and complex glycosylation. The mutants with large deletions also exhibited dramatically increased plasma membrane localization, which was not recapitulated in the panel of mutants with small deletions. A large deletion did not prevent constitutive internalization, suggesting the increase in plasma membrane protein is due to forward trafficking flux. The results indicate an important role of the upper lobe of the ligand binding domain in regulating mGluR6 secretory trafficking, and suggest that disruption of the structure of this domain leads to unconventional trafficking. These findings are consistent with an intraluminal interaction regulating mGluR6 sorting within the endoplasmic reticulum.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"136 ","pages":"Article 104068"},"PeriodicalIF":2.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834410","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":"Acute stress uncovers latent β2-adrenergic receptor and Corticotropin Releasing Factor interactions in the ventral Bed Nucleus of the Stria Terminalis critical for long-term stress-avoidance behavior","authors":"Opeyemi Showemimo,&nbsp;Angela E. Snyder,&nbsp;Arisha Tariq,&nbsp;Sarah S. Bingaman,&nbsp;Amy C. Arnold,&nbsp;Anirban Paul,&nbsp;Jonathan E. Ploski,&nbsp;Yuval Silberman","doi":"10.1016/j.mcn.2025.104069","DOIUrl":"10.1016/j.mcn.2025.104069","url":null,"abstract":"<div><div>β-adrenergic receptor (β-AR) and corticotropin-releasing factor (CRF) regulation of excitatory glutamatergic neurotransmission in the Bed Nucleus of the Stria Terminalis (BNST) is critical for many stress-related behaviors. While β-AR/CRF interactions are well-documented in the dorsal BNST, few studies have examined this interaction in the ventral BNST (vBNST), the subregion with the highest abundance of norepinephrine (NE) inputs. We hypothesized that the extensive NE innervation of the vBNST may result in distinct mechanisms of β-AR/CRF interactions regulating glutamate transmission that may be relevant for stress-related behaviors. To test this hypothesis, we used electrophysiological, behavioral, and pharmacological approaches in stress-naïve and stress-exposed wild-type and transgenic mice. We found that in stress-naïve mice, β1-ARs drive vBNST glutamatergic transmission, whereas β2-ARs are required to enhance vBNST glutamate transmission in mice after acute stress. Both mechanisms require CRF signaling. Confirmed by in situ hybridization, these data indicate a novel mechanism whereby acute stress upregulates β2-ARs in CRF neurons to drive vBNST excitability. To assess the behavioral relevance of this mechanism, mice were tested for stress avoidance behavior in a novel combinatorial stress exposure model, where we found that only mice exposed to two simultaneous stressors within a single stress-exposure session showed long-term place avoidance behavior at 1, 7, and 28 days later. This effect was lost in mice with knockdown of β2-AR expression in CRF cells or in wild-type mice treated with a β2-AR antagonist after stress exposure. Taken together, our findings reveal a novel mechanism by which stress uncovers latent β2-AR/CRF enhancement of vBNST excitatory neurotransmission to induce long-term stress avoidance behavior.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"136 ","pages":"Article 104069"},"PeriodicalIF":2.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906284","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":"Precision therapeutic strategies for Alzheimer's disease: Amyloid β–targeted foundations and multimodal next-generation approaches","authors":"Imran Zafar ,&nbsp;Muhammad Sohail Khan ,&nbsp;Adil Jamal ,&nbsp;Shaista Shafiq ,&nbsp;Fayez Saeed Bahwerth ,&nbsp;Najeeb Ullah Khan","doi":"10.1016/j.mcn.2025.104070","DOIUrl":"10.1016/j.mcn.2025.104070","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is the leading cause of dementia and a significant unmet medical challenge, pathologically characterized by amyloid β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction, and chronic neuroinflammation. Although Aβ has long been a central therapeutic target, clinical translation has historically been hindered by late-stage intervention, inadequate blood–brain barrier (BBB) penetration, and the molecular heterogeneity of AD. Recent advances with Aβ-targeted monoclonal antibodies, particularly lecanemab and donanemab, have provided the first clinical evidence of disease modification, demonstrating robust amyloid clearance and measurable slowing of cognitive decline in early-stage AD. These results validate the Aβ hypothesis but also highlight persistent barriers, including amyloid-related imaging abnormalities (ARIA), questions about the durability of benefit, challenges in patient stratification, and the high economic burden of biologics. To overcome these limitations, next-generation strategies are emerging that extend beyond single-pathway targeting toward multimodal and precision-based frameworks. Innovative approaches include tau-directed therapies to prevent the propagation of neurofibrillary tangles, immunomodulatory strategies to enhance microglial clearance of aggregated proteins, and neuroprotective interventions to counteract oxidative and inflammatory stress. Concurrently, nanotechnology-based drug delivery systems are being engineered to efficiently traverse the BBB and deliver multifunctional payloads, while artificial intelligence (AI)– driven discovery platforms are accelerating target identification, biomarker integration, and patient stratification. Future perspectives emphasize the importance of preclinical-stage intervention, long-term efficacy trials, and the adoption of personalised treatment paradigms that integrate genomic, biomarker, and digital profiling to optimise outcomes. Collectively, these advances signal a paradigm shift in AD therapeutics, positioning Aβ-targeted therapies as a foundation while paving the way for combination strategies that more effectively address the disease's multifactorial nature.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"136 ","pages":"Article 104070"},"PeriodicalIF":2.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889402","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}