Schistosoma mansoni Larval Extracellular Vesicle protein 1 (SmLEV1) is an immunogenic antigen found in EVs released from pre-acetabular glands of invading cercariae

Extracellular Vesicles (EVs) are an integral component of cellular/organismal communication and have been found in the excreted/secreted (ES) products of both protozoan and metazoan parasites. Within the blood fluke schistosomes, EVs have been isolated from egg, schistosomula, and adult lifecycle stages. However, the role(s) that EVs have in shaping aspects of parasite biology and/or manipulating host interactions is poorly defined. Herein, we characterise the most abundant EV-enriched protein in Schistosoma mansoni tissue-migrating schistosomula (Schistosoma mansoni Larval Extracellular Vesicle protein 1 (SmLEV1)). Comparative sequence analysis demonstrates that lev1 orthologs are found in all published Schistosoma genomes, yet homologs are not found outside of the Schistosomatidae. Lifecycle expression analyses collectively reveal that smlev1 transcription peaks in cercariae, is male biased in adults, and is processed by alternative splicing in intra-mammalian lifecycle stages. Immunohistochemistry of cercariae using a polyclonal anti-recombinant SmLEV1 antiserum localises this protein to the pre-acetabular gland, with some disperse localisation to the surface of the parasite. S. mansoni—infected Ugandan fishermen exhibit a strong IgG1 response against SmLEV1 (dropping significantly after praziquantel treatment), with 11% of the cohort exhibiting an IgE response and minimal levels of detectable antigen-specific IgG4. Furthermore, mice vaccinated with rSmLEV1 show a slightly reduced parasite burden upon challenge infection and significantly reduced granuloma volumes, compared with control animals. Collectively, these results describe SmLEV1 as a Schistosomatidae-specific, EV-enriched immunogen. Further investigations are now necessary to uncover the full extent of SmLEV1’s role in shaping schistosome EV function and definitive host relationships.

The Synaptic Vesicle Protein 2A Interacts With Key Pathogenic Factors in Alzheimer’s Disease: Implications for Treatment

Alzheimer’s disease (AD), a serious neurodegenerative disease, is pathologically characterized by synaptic loss and dysfunction. Synaptic vesicle protein 2A (SV2A) is an indispensable vesicular protein specifically expressed in synapses and can be used as a biomarker for synaptic density. We found that the expression of SV2A was down-regulated in the hippocampus of AD patients, yet the relation of SV2A to other hallmarks of AD pathology such as amyloid precursor protein (APP), β-amyloid (Aβ), and Tau protein is not thoroughly clear. In addition, SV2A colocalized with APP and was down-regulated at Aβ deposition. Moreover, we found that SV2A deficiency leads to a simultaneous increase in Aβ and Tau hyperphosphorylation, while SV2A overexpression was associated with downregulation of β-site APP cleaving enzyme 1 and apolipoprotein E genes. In addition, evidence gained in the study points to the phosphatidylinositol 3-kinase signaling pathway as a possible mediator in SV2A regulation influencing the incidence and development of AD. With limited effective diagnostic methods for AD, a close interplay between SV2A and AD-related proteins demonstrated in our study may provide novel and innovative diagnostic and therapeutic opportunities.

Synaptic Vesicle Protein 2A Expression in Glutamatergic Terminals Is Associated with the Response to Levetiracetam Treatment

Synaptic vesicle protein 2A (SV2A), the target of the antiepileptic drug levetiracetam (LEV), is expressed ubiquitously in all synaptic terminals. Its levels decrease in patients and animal models of epilepsy. Thus, changes in SV2A expression could be a critical factor in the response to LEV. Epilepsy is characterized by an imbalance between excitation and inhibition, hence SV2A levels in particular terminals could also influence the LEV response. SV2A expression was analyzed in the epileptic hippocampus of rats which responded or not to LEV, to clarify if changes in SV2A alone or together with glutamatergic or GABAergic markers may predict LEV resistance. Wistar rats were administered saline (control) or pilocarpine to induce epilepsy. These groups were subdivided into untreated or LEV-treated groups. All epileptic rats were video-monitored to assess their number of seizures. Epileptic rats with an important seizure reduction (>50%) were classified as responders. SV2A, vesicular γ-aminobutyric acid transporter and vesicular glutamate transporter (VGLUT) expression were assessed by immunostaining. SV2A expression was not modified during epilepsy. However, responders showed ≈55% SV2A-VGLUT co-expression in comparison with the non-responder group (≈40%). Thus, SV2A expression in glutamatergic terminals may be important for the response to LEV treatment.

The Synaptic Vesicle Protein 2a Interacts With Key Pathogenic Factors in Alzheimer’s Disease: Implications for Treatment

Background:Alzheimer’s Disease(AD), a serious neurodegenerative disease,is pathologicallycharacterized by synaptic loss and dysfunction.Synaptic vesicle protein 2A (SV2A) is an indispensable vesicular protein specifically expressed in synapses and can be used as a biomarker for synaptic density. Nevertheless, the involvement of SV2A in the pathogenesis and development of ADand its relation to other hallmarks of AD pathology, such as amyloid precursor protein (APP), β-amyloid (Aβ), and tau protein are not fully understood.Methods:We first examined and compared the mRNA levels of SV2A in the hippocampus of AD patients and non-AD subject in the Allen Brain database,thenwe constructed SV2A knockout mouse model.Using PET imagingwe compared the expression of Aβ in SV2A knockout mice and WT mice, analyze the relationship between SV2A and AD related proteins by quantitative real-time polymerase chain reaction (PCR), western blotting and ELISA.Results:Our results showed thatthe expression of SV2A was downregulated in the hippocampus of AD patients.In addition,SV2A colocalized with APPandwas downregulated at Aβ deposition. Moreover, we used APPswe293T cells lines to either silence or overexpress SV2A and found that SV2A deficiency leads to a simultaneous increase in Aβand Tau hyperphosphorylation,whileSV2A overexpression was associated with down-regulation of BACE1 and APOE. In addition, evidence gained in the study points PI3K signaling pathway as a possible mediator in SV2A regulation influencing the incidence and development of AD. Conclusions:Our research demonstrated that SV2A is an important regulator of AD, close interplay between SV2A and AD related proteins demonstrated in our studyprovide novel diagnostic and therapeutic opportunities of AD. This study provides guidelines and information regarding the mechanism of SV2A influence in the regulation of AD and possible future research of neurological diseases.