Levels of nicastrin species are increased in Alzheimer’s disease cerebrospinal fluid

Abstract

AbstractBackgroundPrevious studies demonstrated that presenilin‐1 (PS1), the active component of the intramembrane γ‐secretase complex, can be detected as soluble heteromeric aggregates in cerebrospinal fluid (CSF). The γ‐secretase components, APH‐1 (anterior pharynx‐defective 1) and PEN‐2 (presenilin enhancer 2), co‐exist within these CSF complexes, while nicastrin is not detected. Nicastrin plays a role in the complex regulation, and substrate recognition, being the unique γ‐secretase component that is a Type I, single‐pass transmembrane protein. Here, we aim to characterize and compare the levels of CSF nicastrin in Alzheimer’s disease (AD) and non‐AD control patients.MethodNicastrin levels were analyzed in the CSF by western blotting using antibodies against the ectodomain and the intracellular domain to identify the different species of the protein that are present in human CSF. Core AD CSF biomarkers (Aβ1‐42, T‐tau, and p‐Tau) were determined. We also assessed whether CSF nicastrin and PS1 are present in extracellular vesicles (EVs).ResultWe show that nicastrin is present in CSF as full‐length species of 130, 110, and 105 kDa. We demonstrated that nicastrin full‐length species are increased in AD patients (n = 21) in comparison with non‐AD controls (n = 21), and that the levels of the three species positively correlated with T‐tau and p‐Tau levels in AD patients. Nicastrin was also found to be present in EVs, different from PS1.ConclusionThe increased levels of nicastrin in the CSF of AD patients confirmed the potential alteration of γ‐secretase subunits during pathology progression. Further studies are required to evaluate whether these proteins could act as biomarkers to facilitate AD diagnosis and/or prognosis.