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Dense core vesicle markers in CSF and cortical tissues of patients with Alzheimer’s disease

Translational Neurodegeneration 2021年第3期10卷 487-501页

作者： Neus Barranco Virginia Plá Daniel Alcolea Irene Sánchez‑Domínguez Reiner Fischer‑Colbrie Isidro Ferrer Alberto Lleó Fernando Aguado Department of Cell Biology Physiology and ImmunologyFaculty of BiologyUniversity of Barcelona08028 BarcelonaSpain Institute of Neurosciences University of Barcelona08028 BarcelonaSpain Memory Unit Department of NeurologySant Pau Biomedical Research Institute.Sant Pau HospitalAutonomous University of Barcelona08041 BarcelonaSpain Center for Net‑worked Biomedical Research on Neurodegenerative Diseases(CIBERNED) 28031 MadridSpain Department of Pharmacology Innsbruck Medical University6020 InnsbruckAustria Department of Pathology and Experi‑mental Therapeutics University of Barcelonaand Bellvitge University HospitalBellvitge Biomedical Research InstituteHospitalet de LlobregatSpain Pre‑sent Address:Center for Translational Neuromedicine University of Rochester Medical CenterRochesterNY 14642USA

Background:New fuid biomarkers for Alzheimer’s disease(AD)that reveal synaptic and neural network dysfunc‑tions are needed for clinical practice and therapeutic trial design.Dense core vesicle(DCV)cargos are promising cerebrospinal fuid(CSF)indicators of synaptic failure in AD patients.However,their value as biomarkers has not yet been determined.Methods:Immunoassays were performed to analyze the secretory proteins prohormone convertases PC1/3 and PC2,carboxypeptidase E(CPE),secretogranins SgIII and SgII,and Cystatin C in the cerebral cortex(n=45,provided by Bellvitge University Hospital)and CSF samples(n=66,provided by The Sant Pau Initiative on Neurodegeneration cohort)from AD patients(n=56)and age-matched controls(n=55).Results:In AD tissues,most DCV proteins were aberrantly accumulated in dystrophic neurites and activated astro‑cytes,whereas PC1/3,PC2 and CPE were also specifcally accumulated in hippocampal granulovacuolar degeneration bodies.AD individuals displayed an overall decline of secretory proteins in the CSF.Interestingly,in AD patients,the CSF levels of prohormone convertases strongly correlated inversely with those of neurodegeneration markers and directly with cognitive impairment status.Conclusions:These results demonstrate marked alterations of neuronal-specifc prohormone convertases in CSF and cortical tissues of AD patients.The neuronal DCV cargos are biomarker candidates for synaptic dysfunction and neurodegeneration in AD.

关键词： Alzheimer’s disease Biomarkers Cerebral cortex Cerebrospinal fuid granulovacuolar degeneration PCSK1 PCSK2 Tau protein

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