Abstract
BackgroundNew fluid biomarkers for Alzheimer's disease (AD) that reveal synaptic and neural network dysfunctions are needed for clinical practice and therapeutic trial design. Dense core vesicle (DCV) cargos are promising cerebrospinal fluid (CSF) indicators of synaptic failure in AD patients. However, their value as biomarkers has not yet been determined.MethodsImmunoassays 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).ResultsIn AD tissues, most DCV proteins were aberrantly accumulated in dystrophic neurites and activated astrocytes, whereas PC1/3, PC2 and CPE were also specifically 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.ConclusionsThese results demonstrate marked alterations of neuronal-specific prohormone convertases in CSF and cortical tissues of AD patients. The neuronal DCV cargos are biomarker candidates for synaptic dysfunction and neurodegeneration in AD.
Highlights
New fluid 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) markers are neuropathologically accumulated in dystrophic neurites and granulovacuolar degeneration (GVD) bodies in the AD cerebral cortex To examine DCV changes in the cerebral cortex of AD patients, we performed Western blotting and immunostaining analyses in homogenates and histological sections from AD patients and age-matched controls
Decreased levels of secretory DCV cargos in cerebrospinal fluid (CSF) from AD patients are associated with neurodegeneration markers we investigated the levels of DCV proteins in 66 CSF samples from phenotypically well-characterized AD patients (n = 33) and cognitively normal controls (n = 33) with immunoblotting and radioimmunoassay methods
Summary
New fluid 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 fluid (CSF) indicators of synaptic failure in AD patients. Their value as biomarkers has not yet been determined. Reliable cerebrospinal fluid (CSF) signatures have been developed for plaque and tangle pathologies and for associated neurodegenerative processes (reduced Aβ1–42 and increased phosphorylated tau (P-tau) and total tau (T-tau) levels, respectively). These core CSF biomarkers are currently routinely used in clinical practice for diagnosis of AD in patients at the mild cognitive impairment or dementia stage of the disease [9]. Novel CSF biomarker candidates for synaptic pathology include axonal and pre- and postsynaptic proteins, such as SNAP-25, Syntaxin 1B, neurogranin and neurofilament light chain [14,15,16,17]
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