Early detection of Alzheimer's disease (AD) is critical for preventing disease progression. Blood platelets have emerged as a useful peripheral source for AD diagnosis. However, the identification of proteomics-based platelet biomarkers of mild cognitive impairment (MCI) and AD in relation to amyloid β (Aβ) deposition remains largely unexplored. In this study, we compared four groups from 18 participants: subjective memory impairment (SMI, n = 4) as cognitive normal controls, MCI without Aβ deposition (MCI-A(+), n = 5), MCI with Aβ deposition (MCI-A(-), n = 5), and AD (n = 4). We conducted in-depth platelet protein profiling using high-throughput LC-MS/MS with tandem mass tag labeling. Among the total 4,524 proteins detected, we identified both unique and overlapping differentially expressed proteins in MCI-A(+), MCI-A(-), and AD compared with SMI. Hierarchical clustering analysis revealed seven distinct patterns of proteomic alterations across groups. Functional network and gene ontology enrichment analyses indicated that each cluster was associated with specific processes, including platelet activation, AD, and apoptotic signaling pathways. Notably, upregulated proteins in MCI-A(-) and AD were linked to endomembrane system organization. Furthermore, we quantified the relative abundance of multiple protein candidates that were significantly altered in MCI-A(-) and AD compared with SMI and MCI-A(+). Our findings highlight several platelet proteins-ATP6V0C, AP4B1, RAB2B, PSMD9, FKBP1B, and mTOR-as potential molecular targets for predicting AD at the stage of MCI with Aβ deposition, providing new insights into amyloid-related neurodegeneration.

Autoimmune diseases (AIDs) result from intricate interactions among genetic, environmental and immune factors, with emerging evidence underscoring the role of the central nervous system (CNS) in their pathogenesis. In this study, we utilized two-sample Mendelian randomization to systematically explore the causal relationships between 3,935 brain imaging-derived phenotypes (IDPs) and eight AIDs, including atopic dermatitis, inflammatory bowel disease, lupus erythematosus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatoid arthritis and type 1 diabetes. We identified nine IDPs with causal associations to eight representative AIDs. Mediation analysis uncovered eight potential immune cells or inflammatory factors bridging IDPs and AIDs. These findings provide compelling evidence for the CNS's involvement in autoimmune progresses through neuro-immune pathways and underscore potential diagnostic and therapeutic targets within the neuro-immune axis. This study introduces a novel framework for investigating interdisciplinary interventions that target CNS-immune interactions in the context of AIDs.

Brain pericytes are mediators of neuroinflammation, as evidenced in vitro, in animal models and humans. We and others have identified the platelet-derived growth factor (PDGF)-BB -PDGF receptor beta (PDGFRB) pathway as a key modulator of inflammatory cues in human brain pericytes. We investigate the receptor for interkeukin-33 (IL-33), interkeukin-1 receptor-like 1 (IL1RL1; also known as ST2) as a highly upregulated transcript in response to PDGF-BB stimulation in pericyte cultures. We show that pericytes express transcripts for both the membrane bound form of the receptor (ST2L) and the soluble form (sST2) that acts as a decoy and blocks IL-33 signalling. Human brain pericytes secrete sST2 in response to PDGF-BB, but also to transforming growth factor alpha (TGF) alpha and interleukin-4 (IL-4), although they are unresponsive to IL-33 treatment. We also examine pericyte expression of both IL1RL1 transcripts using RNAscope in two different in vivo models of neuroinflammation, experimental autoimmune encephalitis (EAE) and photothrombotic stroke. We present data showing that in rodents pericytes increase transcript expression predominantly for soluble IL1RL1 in inflammatory and stroke models. Our results highlight a novel expression pattern of the soluble and membrane bound forms of the IL-33 receptor in vitro and in combination with our observations in vivo suggest that cerebrovascular pericytes may negatively regulate IL-33 signalling following injury or inflammatory insults to the brain.

Artificial intelligence (AI) is transforming biomarker discovery in neurology by overcoming key limitations of conventional approaches that are often slow, reductionist, and unable to integrate complex multimodal data. In this narrative review, we searched the data bases; PubMed, Scopus, IEEE Xplore, CINAHL, Embase and the Cochrane Library from inception to 2025 to evaluate how AI supports biomarker identification, diagnosis, prognostication, and treatment stratification across neurovascular, neurodegenerative, neuro-oncological and seizure disorders. Evidence demonstrates that AI-driven imaging and multi-omics biomarkers can detect disease earlier, improve prediction accuracy, and support personalised care. For example, AI models improve stroke outcome prediction beyond conventional scores, identify intracranial aneurysms with sensitivities exceeding 90%, predict conversion from mild cognitive impairment to Alzheimer's disease with accuracies approaching 85-90%, and extract radiogenomic biomarkers in gliomas that outperform traditional diagnostic strategies. However, real-world translation remains constrained by dataset bias, limited external validation, interpretability challenges, and gaps in generalisability, particularly in underrepresented populations. Overall, AI-driven biomarker discovery offers a powerful pathway toward precision neurology, with the greatest impact expected when technical innovation is paired with robust clinical validation, regulatory integration, and equitable data representation.

Long-lasting synaptic changes enable memory storage and regulate recall in the brain. Our previous work established that generation of multi-innervated dendritic spines (MISs), spines with typically two excitatory presynaptic inputs, underlies hippocampal memory formation in aged, but not young mice. The identification of MIS generation was done by ultrastructural analysis in hippocampal CA1 stratum radiatum 24 h after contextual fear conditioning (CFC). However, our analysis did not consider multi-spine boutons (MSBs), which were recently shown to increase in complexity (complex MSBs are pre-synaptic boutons connecting with more than two post-synapses) at a later time point after CFC in young age. Therefore, we re-analyzed our three-dimensional electron microscopy images and show that, unexpectedly, MSB complexity, decreases in CA1 stratum radiatum 24 h after CFC. The decrease in MSB complexity occurred both in young and aged mice, indicating that aging has no impact on this synaptic change. Considering that complex MSBs link the activity of multiple postsynaptic neurons, we suggest that after CFC a decrease in MSB complexity may be required for specific memory recall.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13041-025-01265-z.

The Voltage-gated sodium channel NaV1.8 is a critical determinant of nociceptive signaling in primary sensory neurons. Here, we evaluated the analgesic potential of suzetrigine, a potent clinically approved NaV1.8 blocker, using electrophysiological, behavioral, and tolerance paradigms in mice. Whole-cell recordings from dorsal root ganglion neurons revealed that suzetrigine inhibited tetrodotoxin (TTX)-resistant sodium currents in a concentration-dependent manner (IC50 = 0.35 ± 0.17 μM), consistent with high-affinity NaV1.8 inhibition. In vivo, intraperitoneal administration of suzetrigine significantly reduced nocifensive behaviors in the formalin test, attenuated CFA-induced thermal hypersensitivity, and reversed mechanical hyperalgesia in the partial sciatic nerve injury-induced neuropathy model. Importantly, repeated dosing did not produce tolerance in a chronic administration paradigm. Although suzetrigine showed limited efficacy in clinical trials for neuropathic pain, its robust analgesic effects in mouse models underscore the challenges of translating preclinical findings to human neuropathic pain, while still supporting the potential of NaV1.8-targeted therapies.

Substance use disorders, particularly drug addiction, are complex neurophysiological conditions characterized by cycles of compulsive drug use, withdrawal symptoms, and relapses. Methamphetamine (MA) addiction evolves through repeated exposure, altering brain circuits related to reward and neuroplasticity. The need for reliable biomarkers to diagnose and monitor MA addiction has become increasingly critical in clinical practice. In this study, we explored the time-dependent transcriptomic changes in the rat striatum immediately after short-term abstinence following MA self-administration. Using a rat model, we conducted RNA sequencing to analyze the transcriptomic alterations in the striatum immediately after the self-administration and short-term abstinence phases (12- and 24-h post-MA). Through protein–protein interaction (PPI) network analysis and gene expression pattern assessment, we identified key genes that demonstrated significant expression changes. These genes were strongly linked to reward mechanisms, synaptic plasticity, and memory processes, suggesting a role in mediating MA-associated behaviors. Understanding the expression dynamics of these genes provides valuable insights into the molecular mechanisms underlying MA addiction and offers a foundation for developing diagnostic tools and therapeutic strategies targeting addiction-related neural adaptations.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13041-025-01249-z.

The ErbB4 gene is a schizophrenia (SCZ) risk gene that interacts with PSD-95 via its C-terminus, a connection disrupted in SCZ patients. To investigate the functional significance of this interaction, we generated a zygotic mutant mouse lacking the terminal valine “V” residue from the ErbB4 TVV motif. The homozygous (homo) mice exhibited disrupted ErbB4‒PSD-95 interactions and SCZ-relevant behavioral deficits, including impairments in motor function, sensory processing, and memory performance. Structural computational analysis further revealed that the mutation altered the structural conformation of the ErbB4 C-terminus, which affected its binding affinity for PSD-95. Mechanistically, the mutation led to up-regulated but less activation of ErbB4 and down-regulated but overactivation of PSD-95, possibly representing a failed compensatory response aiming to maintain the ErbB4-PSD-95 interaction. Additionally, homo mice presented NMDAR2A subunit specific hypofunction and reduced GAD67 expression. These findings highlight that the ErbB4–PSD–95 interaction is a critical molecular link in the synaptic dysfunction and behavioral abnormalities associated with SCZ.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13041-025-01238-2.

We previously demonstrated that ibrutinib has therapeutic efficacy against AD pathologies when injected intraperitoneally at a lower dosage (10mg/kg, daily for 2 weeks) or orally at a higher dosage (30mg/kg, daily for 1 month) in AD mice models. However, the effect of chronic lower dose of ibrutinib by oral administration on AD pathologies has not been investigated yet. Therefore, we investigated whether long-term oral administration of ibrutinib at a lower dose (1 or 10mg/kg, daily for 5 months) on AD pathology and in vivo toxicity in 5xFAD mice. We found ibrutinib enhanced cognitive function and alleviated Aβ pathology in 5xFAD mice without hepatotoxicity. Furthermore, ibrutinib-treated 5xFAD mice decrease tau hyperphosphorylation, p-GSK3α/β levels, and markers of neuroinflammation such as Iba-1, GFAP, and NLRP3. Collectively, these translational studies indicate chronic oral administration of ibrutinib at low doses improves cognitive function and suppresses AD pathology/neuroinflammation in an AD mice model thereby having potential as an effective multitarget AD therapeutic in clinical application.

Hypothalamic neuropeptides play a pivotal role in regulating appetite and energy homeostasis. Extracellular ATP, a key signaling molecule in the hypothalamus, is associated with neuronal activity and metabolic processes. However, its role in appetite control remains unclear. This study explored how sustained extracellular ATP regulates the expression of hypothalamic orexigenic neuropeptides Agrp and Npy. The administration of ATP alone reduced food intake, body weight, and orexigenic neuropeptide expression in mice. Conversely, inhibition of ATP conversion into AMP using the ectonucleoside triphosphate diphosphohydrolase inhibitor ARL67156 caused a transient increase in these parameters. Prolonged extracellular ATP was shown to upregulate Agrp and Npy expression via purinergic P2X4 receptor (P2X4R) activation in AGRP/NPY-expressing cells. Activation of P2X4R induced CaMKII phosphorylation, which subsequently led to CREB phosphorylation and upregulation of orexigenic neuropeptides. Our findings reveal a mechanism whereby extracellular ATP accumulation promotes appetite through P2X4R-CaMKII-CREB signaling, shedding light on how extracellular ATP impacts hypothalamic appetite control.