Beyond the plate: Genomic characterization of an extensive school Clostridium perfringens type F outbreak.

Purpose: Microglial cells play a crucial role in responding to brain hypoxia. This study aimed to evaluate the effect of RNA-binding proteins (RBPs) on the resistance of microglial cells to hypoxia. Methods: Newborn rats were subjected to hypoxia under four conditions: hypoxia (H), one week after hypoxia induction (H1), control (C), and control one week after hypoxia induction (C1). Microglial cells were isolated and cultured, and exosomes were extracted from brain samples of healthy newborn rats of C1 group. RBPs were extracted from the aforementioned groups and transferred into the microglial cells using exosomes from the C1 group. Cell viability, expression of specific RBP genes, and innate immune factors were evaluated in the studied groups. Additionally, exosomes containing RBPs were injected into the hypoxic rats to investigate behavioral changes in-vivo. Results: The treatment of microglial cells with C1 exosomes elevated the viability rate. The RBP-H proteins significantly elevated the expression of the CPE, HIF-1α, PDI, and VEGF-A genes. Improvements in anti-protease activity, along with decreases in lysozyme and myeloperoxidase activity, were observed in hypoxic microglial cells following treatment with RBP-H and exosomes containing RBP-H. In vivo evaluations revealed that the hypoxic group treated with exosome loading with RBP-H exhibited significant improvements in recognition and balance maintenance. Conclusion: The RBPs may be considered a promising option for further studies in the treatment of brain disorders resulting from hypoxia.

BackgroundThe global aging population is increasingly inflicted with Alzheimer’s disease (AD), but a cure is still unavailable. Neurotrophic factor-α1/carboxypeptidase E (NF-α1/CPE) gene therapy has been shown to prevent and reverse memory loss and pathology in AD mouse models. However, the mechanisms of action of NF-α1/CPE are not fully understood. We investigated if a non-enzymatic form of NF-α1/CPE-E342Q is efficient in reversing AD pathology and carried out a proteomic study to uncover the mechanisms of action of NF-α1/CPE in AD mice.MethodsAAV-human NF-α1/CPE or a non-enzymatic form, NF-α1/CPE-E342Q, was delivered into the hippocampus of 3 × Tg-AD male mice. The effects on cognitive function, neurodegeneration, synaptogenesis and autophagy were investigated. A quantitative proteomic analysis of the hippocampus was carried out.ResultsHippocampal delivery of AAV-NF-α1/CPE-E342Q prevented memory loss, neurodegeneration and microglial activation in 3 × Tg-AD mice, indicating that the action is independent of its enzymatic activity. Quantitative proteomic analysis of the hippocampus of 3 × Tg-AD mice revealed differential expression of > 2000 proteins involving many metabolic pathways after NF-α1/CPE gene therapy. Of these, two new proteins, Snx4 and Trim28, which increase Aβ production and tau levels, respectively, were down-regulated by NF-α1/CPE. Western blot analysis verified their reduction in AAV-NF-α1/CPE-treated 3 × Tg-AD mice compared to untreated mice. Our proteomic analysis indicated synaptic organization as the top signaling pathway altered in response to CPE expression. Synaptic markers PSD95 and Synapsin1 were decreased in 3 × Tg-AD mice and were restored with AAV-NF-α1/CPE treatment. Proteomic analysis hypothesized involvement of autophagic signaling pathway. Indeed, multiple protein markers of autophagy were down-regulated in 3 × Tg-AD mice, accounting for impaired autophagy. NF-α1/CPE gene therapy upregulated the levels of these proteins in 3 × Tg-AD mice, thereby reversing autophagic impairment.ConclusionsThis study uncovered vast actions of NF-α1/CPE in restoring expression of networks of critical proteins including those necessary for maintaining neuronal survival, synaptogenesis and autophagy, while down-regulating many proteins that promote tau and Aβ accumulation to reverse memory loss and AD pathology in 3 × Tg-AD mice. AAV-NF-α1/CPE gene therapy uniquely targets many metabolic levels, offering a promising holistic approach for AD treatment (Graphical ).Graphical abstractSupplementary InformationThe online version contains supplementary material available at 10.1186/s40035-025-00520-6.

Clostridium perfringens (C. perfringens) is spore forming, toxin producing bacterium causing serious diseases in both animals and man and its presence in bats, especially the Egyptian fruit bat, are ecologically important yet increasingly interact with human environments due to habitat changes which raise the concerns about their role as reservoirs for zoonotic pathogens. This study, the first of its kind in Egypt, investigates the occurrence and characteristics of C. perfringens in bats to evaluate their potential role as reservoirs for this toxin-producing, environmentally persistent foodborne pathogen. Fifty fruit bats were captured using mist nets at foraging and roosting sites. The bats were identified morphologically, and for each bat, fecal swabs and internal organs were collected (n = 100). The samples were examined bacteriologically to investigate the C. perfringens detection then confirmed biochemically and via gram staining. DNA was extracted, and toxin genotyping was conducted using multiplex PCR for main toxin genes " cpa, cpb, etx, ia, netB, cpe" whereas uniplex PCR for cpb2. Sequencing and phylogenetic analysis of cpb2 gene from four isolates were analyzed to determine genetic relatedness. Out of 100 samples examined, C. perfringens was detected in 31% (31/100) of samples, with similar occurrence in internal organs (30%) and fecal swabs (32%). All isolates carried the cpa gene (100%), while cpb, cpe, and cpb2 were detected in 83.9%, 64.5%, and 64.5% of isolates, respectively; ia, etx, netB genes were not detected. Notably, 35.5% of isolates harbored both cpe and cpb2 genes. Toxinotyping showed type C as predominant (83.9%), followed by type F (12.9%) and type A (3.2%), highlighting the epidemiological significance of type C strains. Phylogenetic analysis of cpb2 sequences indicated high genetic similarity among bat isolates and close relationships with strains from domestic animals and environmental sources, suggesting possible shared habitats and horizontal gene transfer. These findings identify bats as potential reservoirs of toxigenic C. perfringens, reinforcing the importance of integrating wildlife into One Health surveillance strategies. This study reports the first detection of C. perfringens from Egyptian fruit bats. Phylogenetic analysis revealed close genetic links to strains from domestic animals and environmental sources and these findings highlight bats' potential role as reservoirs of virulent C. perfringens.

Aims/hypothesisResidual pancreatic beta cells in type 1 diabetes show reduced insulin production but the mechanisms remain unclear. Beta cells undergo stress responses during type 1 diabetes, including endoplasmic reticulum (ER) stress and DNA damage-associated senescence, which may affect insulin production. ER stress reduces insulin production but whether senescence disrupts insulin production in human beta cells has not been investigated.MethodsDNA damage-mediated senescence was induced using bleomycin in human donor islets. Relative levels of prohormone convertase 1/3 (PC1/3), prohormone convertase 2 (PC2), carboxypeptidase E (CPE) and the endogenous PC1/3 inhibitor, proprotein convertase subtilisin/kexin type 1 inhibitor (proSAAS), were quantified by western blot. Levels of proinsulin and insulin were measured by ELISA. Flow cytometry was used to measure insulin expression in islet cells. FACS was used to sort endogenous senescent beta cells from islets for analysis of insulin content. Proinsulin immunofluorescence staining was quantified in endogenous senescent vs non-senescent beta cells in pancreas tissue from control donors and donors with type 1 diabetes. Publicly available datasets were used to interrogate relationships between senescence effectors, proinsulin-processing genes and insulin content. DNA damage was induced with bleomycin in the non-proliferative female-fetus-derived EndoC-βH5 human beta cell model to study the impact of the DNA damage response on insulin production in clonal cells growth-arrested due to p16INK4A expression.ResultsDNA damage-mediated senescence led to increased PC1/3 without changes in levels of PC2, CPE or proSAAS in human islets. Consistent with these changes, no significant differences in proinsulin or insulin content were observed, compared with control islets. Flow cytometry confirmed maintenance of insulin content in DNA damage-mediated senescent beta cells vs control cells and sorted endogenous senescent beta cells had similar insulin content to non-senescent beta cells. Proinsulin staining was similar in endogenous senescent vs non-senescent beta cells from a control donor and donor with type 1 diabetes. Analysis of proteomics datasets from Humanislets.com and single-cell RNA-seq datasets from the Human Pancreas Analysis Program corroborated these findings. In EndoC-βH5 beta cells, which are growth-arrested, DNA damage led to decreased levels of CPE and proSAAS, and reduced levels of insulin.Conclusions/interpretationOur findings suggest that the expression of proinsulin-processing enzymes and the production of insulin are sustained in both chemically induced DNA damage-related senescence and in endogenous senescent adult human beta cells. Collectively, these findings suggest that senescent beta cells may be a source of insulin production among residual beta cells in type 1 diabetes.Graphical Supplementary InformationThe online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-025-06603-3.

Alzheimer neurodegenerative disease (AD) has had a major impact worldwide, with no effective drugs for treatment. We discovered and reported earlier that neurotrophic factor-α1 (NF-α1)/carboxypeptidase E (CPE) reversed neurodegeneration and cognitive dysfunction in AD mouse models. We then predicted computationally and validated experimentally that CPE interacts with a pharmacophore of six residues on the 5-HT1E receptor (HTR1E) to activate the ERK-BCL2 signaling pathway leading to protection of human neurons against oxidative stress-induced cell death. We now report using this pharmacophore for in silico virtual screening of ~6 million small molecules to discover candidates with similar binding and neuroprotective properties as CPE. This in silico search identified a molecule (Z124) that was verified experimentally to bind to HTR1E with protective efficacy comparable to NF-α1/CPE but requiring a higher concentration. Next, we carried out R-group design optimization based on Z124 to identify 4 compounds predicted to have much better efficacy than Z124. These compounds were synthesized and tested for neuroprotective activity. All four compounds showed binding to HTLA-HTR1E cells comparable to CPE. We determined the Kd for two of these compounds: R9, 1.38 ± 0.2 nM, and R10, 2.1 ± 0.2 nM, to be over 15 times better than CPE. Furthermore, all four new compounds showed protective activity against oxidative stress-induced cytotoxicity in human HEK293 cells stably transfected with HTR1E, as well as human primary neurons. Mechanistically, R9 and R10 activated ERK phosphorylation and increased the mitochondria prosurvival protein, BCL2, making them excellent candidates for further development as a drug to treat neurodegenerative diseases.

Intravital imaging of the spatiotemporal dynamics of fibrinolysis in a murine model of vascular injury

Clostridium perfringens is responsible for various diseases. Foodborne outbreaks (FBOs) result from the in situ production of C. perfringens enterotoxin (CPE) by type F strains during sporulation. The cpe gene can be plasmidic (p-cpe) or chromosomal (c-cpe). Strains (c-cpe) exhibit greater heat resistance and are frequently associated with FBO. Strains cpe-negative are considered heat-sensitive. This study investigates the sporulation abilities and heat resistance of eight C. perfringens strains isolated from French foodborne outbreaks. Whole-genome sequencing classified the strains into two clades: the “chromosomal cpe clade,”, mainly composed of cpe-positive strains with c-cpe and some cpe-negative strains, and the “plasmidic cpe clade,”, primarily containing cpe-negative strains and a few with plasmid-borne cpe. Sporulation assays and thermal inactivation kinetics were performed on FBO strains to evaluate the influence of genetic variability on sporulation abilities and heat resistance. Experimental analyses revealed that strains within the “chromosomal cpe clade” exhibited the highest sporulation abilities, regardless of cpe presence, while those in the “plasmidic cpe clade” had low sporulation ability. Moreover, heat-resistant spores were produced exclusively by strains of the “chromosomal cpe clade,” with c-cpe strains exhibiting the highest heat resistance (δ95 °C ≈ 49 min), followed by cpe-negative strains (δ95 °C ≈ 9.5 min). p-cpe strains exhibited a heat-sensitive phenotype, with δ85 °C values of 12 min. A key finding of this study is the identification of a group with intermediate heat resistance, distinct from the highly heat-resistant (c-cpe) and heat-sensitive (p-cpe) strains. This intermediate heat-resistance phenotype, observed in cpe-negative strains within the “chromosomal cpe clade,” offers a new perspective on C. perfringens stress adaptation, suggesting their potential for persistence in food. Their heat resistance, along with the potential for cpe gene transfer, could make these strains a relevant hazard for cooked, cooled, and re-heated meat products.

The release of anabaenopeptins (APs) into source freshwater from cyanobacteria harmful algal blooms (cHABs) has raised concerns due to their reported abundance and inhibitory activity toward carboxypeptidases (CP). This study aimed to determine if chlorination, a widely used drinking water treatment, of AP-A, AP-B, and AP-679 inactivates their ability to inhibit carboxypeptidases A (CPA) and B (CPB). Each chlorinate treated AP's degradation by-products (DBPs) were analyzed via high-resolution mass spectrometry (HRMS) to track structural changes. This analysis suggested that site-specific chlorination begins with tyrosine residues. The resulting DBPs for each AP were then tested with standard enzyme assays to observe inhibitory changes to CPA and CPB. It was observed that AP-B DBPs retained potent inhibition of CPB. The lack of chlorine efficacy in inactivating AP-B is attributed to the ureido group arginine being unaffected by chlorination. As cHABs continue to pose global risks to drinking water supplies, further research is needed on AP inactivation, AP removal by drinking water treatment processes, and the impact of CP inhibition on human health.

This study was designed for the isolation and molecular identification of Clostridium perfringens. From a total of 200 samples, C. perfringens was isolated from 30 samples (25%) of laying hens and confirmed using a PCR assay by amplifying a segment of a gene (16S rDNA gene) from C. perfringens. The result of histopathology study showed severe necrotic area surrounded by inflammatory cells, erosions of the intestinal epithelium, ulceration of the epithelium, villous necrosis finding surrounded by inflammatory cells, vascular congestion, goblet cell hyperplasia. For the type of toxin, the bacterial isolates were analyzed by PCR using specific primers in order to determine the presence of cpa genes (cpb, iA, cpe, cpb2). Among the 30 C. perfringens isolates, 10 isolates were identified (33.33%) with C. She is type A (carrying the alpha toxin gene). Of these 10 isolates, 5 isolates (50%) were identified as type A simplex and 5 (50%) were identified as heterozygous but no None of the isolates carry both cpb2 and cpe genes. As the dominant species, 20 isolates (66.66%) were identified as C. The research concluded that C. perfringens was one of the most important isolates from laying hens, and the toxin type A was identified as heterozygous (carrying cpb2), and type C is the most prevalent toxin in Basrah, and the detected toxins cause pathological changes in the intestine.

There is an unmet need for new methods to predict disease course in patients with neuroendocrine tumors (NET). We investigated 92 putative cancer‐related plasma proteins including chromogranin A (CgA) and clinical parameters at the time of diagnosis to identify early factors associated with progressive (PD) or stable disease (SD). Patients with NET grade 1 and 2 of the small intestine (siNET) and pancreas (pNET) were included in this prospective study. Blood samples were obtained at the time of diagnosis before tumor‐related therapy was initiated. During 3 years of follow‐up, SD or PD was determined according to current clinical practice by each investigator. Association rule mining (ARM) was used to identify combinations of biomarkers and clinical parameters associated with SD or PD. Altogether, 115 patients with siNET and 30 with pNET with complete clinical and biomarker data were included in the analysis representing 3 years of follow‐up. Several novel plasma proteins and clinical factors were associated with either PD or SD. In siNET, CgA (>4 upper limits of normal [ULN]) was the most frequent biomarker associated with PD. Females, in contrast to males, with CgA >4 ULN showed a high risk of progression (PPV 100%, NPV 63%). In the siNET cohort, Carboxypeptidase E (CPE) was a discriminating factor between SD and PD. CPE <3.03 was associated with SD, whereas CPE >3.14 was associated with PD (p = 0.003). In the pNET cohort, among clinical variables, only the presence of liver metastasis was associated with PD. CgA was not among the top biomarkers associated with PD. Several parameters, both clinical and biomarker data, as well as combinations of these, were associated with PD or SD 3 years after diagnosis. We identified novel biomarkers improving the association with PD or SD. [Correction added on 28 August 2025, after first online publication: has been updated.]

Prevalence and antimicrobial resistance patterns of Clostridium perfringens from healthy broiler chickens: A potential public health threat

The rice asura mutant, which shows an increased number of stigmas, was found to contain a T-DNA insertion in one of the two alleles of the Os01g0833500 gene, encoding a serine carboxy peptidase II-like protein, SCP5. In the mutant allele, a T-DNA was inserted in the region between Chains A and B domains, resulting in the generation of an aberrant transcript with a stop codon downstream of the Chain A domain region. In the asura mutant, the transcripts corresponding to the Chain A domain were more abundant than those corresponding to the Chain B domain. From the mutant gene, an additional protein consisting only of the Chain A domain was expected to be produced. This was predicted to recognize the substrates but did not exhibit catalytic activity. The same phenotype of increased stigma numbers was detected in both the transformants overexpressing the Chain A domain region in SCP5 and in genome-edited mutants in which the downstream region of the Chain A domain was disrupted. SCP5 interacted with several regulatory proteins involved in flower morphogenesis. Furthermore, a protein consisting only of the Chain A domain interacted with these proteins. These findings imply that excess production of the Chain A domain protein in the asura mutant impairs the function of these regulatory proteins, resulting in insufficient control of stigma number within spikelets.

BackgroundThe global aging population is increasingly inflicted with Alzheimer’s disease (AD), but a cure is still unavailable. Neurotrophic Factor-α1/carboxypeptidase E (NF-α1/CPE) gene therapy has been shown to prevent and reverse memory loss and pathology AD mouse models However, the mechanisms of action of NF-α1/CPE are not fully understood. We investigated if a non-enzymatic form of NF-α1/CPE-E342Q is efficient in reversing AD pathology and carried out a proteomic study to uncover the mechanisms of action of NF-α1/CPE in AD mice.MethodsAAV-human NF-α1/CPE and a non-enzymatic form, NF-α1/CPE -E342Q were delivered into hippocampus of 3xTg-AD mice and effects on cognitive function, neurodegeneration, synaptogenesis and autophagy were investigated. A quantitative proteomic analysis of hippocampus of 3xTg-AD mice with and without AAV-NF-α1/CPE treatment was carried out.ResultsHippocampal delivery of AAV-NF-α1/CPE-E342Q prevented memory loss, neurodegeneration and increase in activated microglia in 3xTg-AD mice, indicating its action is independent of its enzymatic activity. Quantitative proteomic analysis of hippocampus of 3xTg-AD mice that underwent NF-α1/CPE gene therapy revealed differential expression of >2000 proteins involving many metabolic pathways. Of these, two new proteins down-regulated by NF-α1/CPE: Nexin4 (SNX4) and Trim28 which increase Aβ production and tau levels, respectively were identified. Western blot analysis verified that they were reduced in AAV-NF-α1/CPE treated 3xTg-AD mice compared to untreated mice. Our proteomic analysis indicated synaptic organization as top signaling pathway altered as a response to CPE expression. Synaptic markers PSD95 and Synapsin1 were decreased in 3xTg-AD mice and were restored with AAV-NF-α1/CPE treatment. Proteomic analysis hypothesized involvement of autophagic signaling pathway. Indeed, multiple proteins known to be markers of autophagy were down-regulated in 3xTg-AD mice, accounting for impaired autophagy. Expression of these proteins were upregulated in 3xTg-AD mice with NF-α1/CPE gene therapy, thereby reversing autophagic impairment.ConclusionsThis study uncovered vast actions of NF-α1/CPE in restoring expression of networks of critical proteins including those necessary for maintaining neuronal survival, synaptogenesis and autophagy, while down-regulating many proteins that promote tau and Aβ accumulation to reverse memory loss and AD pathology in 3xTg-AD mice. AAV-NF-α1/CPE gene therapy uniquely targets many metabolic levels, offering a promising holistic approach for AD treatment.

Integrative approaches unravelling tea drought alleviation mechanisms primed by carbonyl volatiles and signal peptide.

Clostridium perfringens strains are classified into seven toxinotypes (A–G) based on the profiles of the six typing toxin genes. Among these toxins, NetB is known as an important virulence factor for necrotic enteritis in chickens, and its gene, netB, is present only in type G strains. CPE is the enterotoxin that causes food-borne affections in humans, and its gene, cpe, is carried by type F strains and occasionally by type C, D, and E strains. However, strains with both netB and cpe are extremely rare; thus, they are not assigned to either toxinotype under the current typing scheme. In 2022, a 69-month-old female Holstein cow in Japan died suddenly, and a C. perfringens strain (CP280) possessing both netB and cpe was isolated for the first time in Japan from the bovine intestinal contents. The CP280 genome was composed of one chromosome and six circular plasmids, and netB and cpe were carried on different plasmids, pCP280-82k and pCP280-55k, respectively. Multilocus sequence typing analysis assigned CP280 to ST21, and all other reported ST21 strains were type G strains. In the phylogenetic analysis using the genomes of 553 C. perfringens strains, CP280 was clustered into a group along with the type G strains from affected birds. The deduced amino acid sequences of NetB and CPE from CP280 were identical to those of NetB and CPE from avian necrotic enteritis cases and human food poisoning cases, respectively, implying the potential of CP280 to cause these diseases. The genetic relatedness of CP280 and type G strains strongly suggests that CP280 was originally type G with the netB-positive plasmid pCP280-82k and later acquired the cpe-positive plasmid pCP280-55k; therefore, CP280 should be treated as a type G strain. We propose to change the requirement for this toxinotype in the toxin-based typing scheme from cpe(−) to cpe(+/−).

IntroductionType F Clostridium perfringens (C. perfringens) represents a significant pathogen in human gastrointestinal diseases, primarily through its cpe gene encoding C. perfringens enterotoxin (CPE). This investigation examined the prevalence, antimicrobial resistance patterns, and genetic characteristics of Type F C. perfringens within the Chinese population.MethodsThe study analyzed 2,068 stool samples collected from 11 provincial hospitals in 2024. Antimicrobial susceptibility testing was conducted following Clinical & Laboratory Standards Institute (CLSI) guidelines, while whole-genome sequencing provided detailed genetic profiles. Evolutionary relationships and clonal transmission patterns were investigated through phylogenetic and genetic environment analyses.ResultsThe prevalence of Type F C. perfringens was 2.38%, with isolates predominantly identified in human clinical samples and higher detection rates in gastroenterology departments. Notably, 47.1% of isolates demonstrated high resistance to metronidazole, while all exhibited intermediate resistance to erythromycin. Phylogenetic analysis revealed high similarity among isolates from patients within the same province (single-nucleotide polymorphism (SNPs)<100), and genetic environment analysis indicated potential horizontal gene transfer between animal and human strains.ConclusionsThis investigation predominantly identified Type F C. perfringens in human clinical cases, with sporadic detection in pets and food products. These findings highlight the emergence of Type F C. perfringens outbreaks among diarrheal patients, emphasizing the necessity for targeted interventions as virulence factors increase.

Background/Objectives: The Pacific white shrimp (L. vannamei) is economically significant, and its growth is regulated by multiple factors. Carboxypeptidase B (CPB) is related to protein digestion, but its gene sequence and features in L. vannamei are not fully understood. This study aimed to explore the molecular and functional properties of CPB in L. vannamei. Methods: The Lv-CPB gene was cloned, and bioinformatics analysis, qRT-PCR, in situ hybridization, recombinant protein expression in Escherichia coli, and an enzyme activity assay were performed. Results: The Lv-CPB gene is 1414 bp long with a 1263 bp ORF encoding a 420-amino-acid protein. It is stable, hydrophilic, and is highly expressed in the hepatopancreas. The recombinant protein was efficiently expressed with a molecular weight of about 47 kDa. The optimal pH and temperature for Lv-CPB were 8.0 and 50 °C, respectively. Conclusions: This study revealed the molecular and functional characteristics of Lv-CPB, providing insights into its role in shrimp digestion, as well as suggestions for improving aquaculture practices.

Protein digestion and amino acid absorption mechanisms along the midgut of Musca domestica larvae

Observational studies have revealed associations between levels of plasma and cerebrospinal fluid (CSF) proteins and cognition-related traits. However, these associations may be influenced by confounding factors inherent in observational research. This study aims to identify plasma and CSF proteins associated with intelligence, fluid intelligence score, and cognitive performance through the application of Mendelian randomization (MR). Proteomic quantitative trait locus (pQTL) data for plasma and CSF proteins were sourced from existing genome-wide association study (GWAS). Intelligence, fluid intelligence score, and cognitive performance GWAS summary statistics provided comprehensive data for two-sample MR analysis. Extensive sensitivity analyses, including Steiger testing, reverse MR analysis, and Bayesian co-localization, were conducted to validate associations and identify shared genetic variants. Phenotype scanning explored potential pleiotropic effects. MR analysis identified several proteins in plasma and CSF significantly associated with intelligence, fluid intelligence scores, and cognitive performance. For intelligence, negatively associated proteins in plasma include endoplasmic reticulum aminopeptidase 2 (ERAP2) and secretogranin III (SCG3), while positively associated proteins are myeloperoxidase (MPO), signal regulatory protein alpha (SIRPA), regulator of microtubule dynamics 1 (RMDN1), and endoplasmic reticulum lectin 1 (ERLEC1). In CSF, C1-esterase inhibitor and carboxypeptidase E (CBPE) both exhibited positive associations with intelligence. For fluid intelligence scores, negatively associated proteins in plasma are copine 1 (CPNE1) and SCG3, while positively associated proteins are nudix hydrolase 12 (NUDT12) and RMDN1.In CSF, Macrophage Stimulating Protein (MSP) demonstrated a significant negative impact. For cognitive performance, negatively associated proteins in plasma include ERAP2, tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1), and SCG3, while positively associated proteins are NUDT12, RMDN1, ERLEC1, and ectonucleotide pyrophosphatase/phosphodiesterase family member 5 (ENPP5). In CSF, C1-esterase inhibitor was positively associated, while MSP and soluble tyrosine kinase with immunoglobulin-like and EGF-like domains 1(sTie-1) showed a negative association. Bayesian co-localization analysis revealed significant genetic overlaps between SIRPA, RMDN1, and ERLEC1 in plasma with intelligence; NUDT12 and SCG3 in plasma with fluid intelligence scores; and TIE1, NUDT12, RMDN1, ERLEC1, and ENPP5 in plasma with cognitive performance. Additionally, significant co-localization was identified between C1-esterase inhibitor and CBPE in CSF with intelligence, as well as between C1-esterase inhibitor and sTie-1 in CSF with cognitive performance. Reverse causality analysis confirmed the causal direction from proteins to cognitive traits. This study identifies specific plasma and CSF proteins that significantly impact intelligence, fluid intelligence scores, and cognitive performance. These proteins could serve as biomarkers and targets for future research and therapeutic interventions aimed at sustaining cognitive abilities and reducing impairment risks.