Blood neuro-exosomal synaptic proteins predict Alzheimer's disease at the asymptomatic stage.

INTRODUCTION: Exosomes are an emerging candidate for biomarkers of Alzheimer's disease (AD). This study investigated whether exosomal synaptic proteins can predict AD at the asymptomatic stage. METHODS: We conducted a two-stage-sectional study (discovery stage: AD, 28; amnestic mild cognitive impairment [aMCI], 25; controls, 29; validation stage: AD, 73; aMCI, 71; controls, 72), a study including preclinical AD (160) and controls (160), and a confirmation study in familial AD (mutation carriers: 59; non-mutation carriers: 62). RESULTS: The concentrations of growth associated protein 43 (GAP43), neurogranin, synaptosome associated protein 25 (SNAP25), and synaptotagmin 1 were lower in AD than in controls (P < .001). Exosomal biomarker levels were correlated with those in cerebrospinal fluid (R2  = 0.54-0.70). The combination of exosomal biomarkers detected AD 5 to 7 years before cognitive impairment (area under the curve = 0.87-0.89). DISCUSSION: This study revealed that exosomal GAP43, neurogranin, SNAP25, and synaptotagmin 1 act as effective biomarkers for prediction of AD 5 to 7 years before cognitive impairment.

SNAP-25 in Serum Is Carried by Exosomes of Neuronal Origin and Is a Potential Biomarker of Alzheimer's Disease.

A loss of synaptic density and connectivity is observed in multiple brain regions of Alzheimer's disease (AD) patients, resulting in a reduced expression of synaptic proteins such as SNAP-25 (synaptosomal-associated-protein-25). SNAP-25 alterations thus could be an index of the degree of synaptic degeneration in the central nervous system (CNS). We isolated from serum of both AD patients and healthy controls (HC) a population of neuron-derived exosomes (NDEs) and measured the concentrations of SNAP-25 contained in such NDEs. The levels of SNAP-25 carried by NDEs were reduced in AD patients (mean 459.05 ng/ml, SD 146.35 ng/ml) compared to HC (mean 686.42 ng/ml, SD 204.08 ng/ml) (p < 0.001). As a further confirmation of these results, ROC (receiver operating characteristic) analyses indicated that the level of SNAP-25 carried by NDEs has the power to discriminate between AD and HC (AUC = 0.826, sensitivity = 87.5%, specificity = 70.6%, p < 0.0001, cut-off value 587.07 ng/ml). Notably, a correlation between the levels of SNAP-25 carried by NDEs and levels and cognitive status measured by MMSE score (r = 0.465, 95% CI 0.11 to 0.714, p = 0.01) was detected. This is the first report of SNAP-25 measurement in serum. These data suggest that NDE-carried SNAP-25 could be an effective and accessible biomarker that reflects synapses integrity in the brain.

Novel SNARE Complex Polymorphisms Associated with Multiple Sclerosis: Signs of Synaptopathy in Multiple Sclerosis

Background: It is well known that axonal degeneration plays a role in disability in patients with multiple sclerosis, and synaptopathy has recently become an important issue. Aims: To investigate the possible roles of selected synaptic and presynaptic membrane protein genetic polymorphisms (VAMP2, SNAP-25, synaptotagmin, and syntaxin 1A) in patients with multiple sclerosis. Study Design: Case-control study. Methods: A total of 123 patients with multiple sclerosis and 192 healthy controls were included. The functional polymorphisms of specific SNARE complex proteins (VAMP2, synaptotagmin XI, syntaxin 1A, and SNAP-25) were analyzed by polymerase chain reaction. Results: Significant differences were detected in the genotype and allele distribution of 26-bp Ins/Del polymorphisms of VAMP2 between patients with multiple sclerosis and control subjects; Del/Del genotype and Del allele of VAMP2 were more frequent in patients with multiple sclerosis (p=0.011 and p=0.004, respectively). Similarly, Ddel polymorphism of SNAP-25 gene C/C genotype (p=0.059), syntaxin 1A T/C and C/C genotypes (p=0.005), and synaptotagmin XI gene C allele (p=0.001) were observed more frequently in patients with multiple sclerosis. CC, syntaxin rs1569061 1A gene for 33-bp promoter region TC haplotypes, and synaptotagmin XI gene were found to be associated with an increased risk for multiple sclerosis (p=0.012). Similarly, GC haplotype for rs3746544 of SNAP-25 gene and rs1051312 of SNAP-25 gene were associated with an increased risk for multiple sclerosis (p=0.022). Conclusion: Genetic polymorphisms of SNARE complex proteins, which have critical roles in synaptic structure and communication, may play a role in the development of multiple sclerosis.

Pilot study: potential transcription markers for adult attention-deficit hyperactivity disorder in whole blood.

Attention-deficit hyperactivity disorder (ADHD) is a common behavioural disorder that affects not only children and adolescents but also adults; however, diagnosis of adult ADHD is difficult because patients seem to have reduced externalized behaviour. ADHD is a multifactorial disorder in which many genes, all with small effects, are thought to cause the disorder in the presence of unfavourable environmental conditions. Therefore, in this pilot study, we explored the expression profile of a list of previously established candidate genes in peripheral blood samples from adult ADHD subjects (n = 108) and compared these results with those of healthy controls (n = 35). We demonstrate that combining the gene expression levels of dopamine transporter (SLC6A3), dopamine D5 receptor, tryptophan hydroxylase-1, and SNAP25 as predictors in a regression model resulted in sensitivity and specificity of over 80 % (ROC: max R(2) = 0.587, AUC = 0.917, P < 0.001, 95 % CI: 0.900-0.985). In conclusion, the combination of these four genes could represent a potential method for estimating risk and could be of diagnostic value for ADHD. Nevertheless, further investigation in a larger independent population including different subtypes of ADHD (inattentive, hyperactive, or combined type) patients is required to obtain more specific sets of biomarkers for each subtype as well as to differentiate between child, adolescent, and adulthood forms.

Association between a synaptosomal protein (SNAP-25) gene polymorphism and verbal memory and attention in patients with endogenous psychoses and mentally healthy subjects.

Synaptosomal protein SNAP-25 is involved in the process of transmitting nerve spikes in the CNS and in the consolidation of memory traces in the hippocampus. Two independent studies have demonstrated associations between SNAP-25 gene polymorphisms and intellectual functions in a group of mentally healthy subjects and patients with schizophrenia. The aim of the present work was to perform a comparative study of the association between the MnlI polymorphism of SNAP-25 and cognitive functions (verbal memory, attention/executive functions) in 66 patients with endogenous psychoses, 75 of their mentally healthy relatives, and 136 healthy control subjects. Statistical analysis showed that the effectiveness of performing cognitive tests was significantly affected by group assignment (p = 0.00001) and genotype (p = 0.012). The interaction between genotype and group assignment also had an influence (p = 0.02). In all groups, carriers of the TT genotype had worse measures than carriers of other genotypes. The similar nature of the influences of the MnlI polymorphism on variations in measures in all groups indicates that this gene is related to overall intellect.

[The association of the SNAP-25 gene polymorphism with verbal memory and attention in patients with major psychosis and healthy people].

The synaptosomal-associated protein (SNAP-25) plays an integral role in synaptic transmission and in memory consolidation in the hippocampus. Recently an association between SNAP-25 gene polymorphism and cognitive ability has been reported in two independent studies of healthy people and patients with schizophrenia. Authors carried out an association study of MnlI SNAP-25 polymorphism and performance on neurocognitive tests measuring verbal memory, attention/executive functions in 66 patients with major psychosis, 75 their relatives and 136 controls. MANCOVA revealed a significant effect of group (small er, Cyrillic=0,00001) and genotype (small er, Cyrillic=0,012) as well as an interaction effect between group and genotype (small er, Cyrillic=0,02) on the performance on neurocognitive tests. Carriers of the TT genotype performed worse on the most tasks compared to other genotypes. The similar character of the MnlI SNAP-25 polymorphism effect on the variability of neurocognitive traits in all groups suggests the relationship between this gene and general cognitive ability.