CSF beta-amyloid levels are altered in narcolepsy: a link with the inflammatory hypothesis?

Abstract

Introduction Autoimmune and inflammatory mechanisms are suggested as a possible cause of the hypocretin cell loss in human narcolepsy. Interestingly, decreased CSF levels of beta-amyloid1–42 (Abeta–42) are described related to brain inflammation. In fact the Abeta–42 metabolism is strongly regulated by inflammatory mechanisms and the inflammatory pathways of the immune system represent targets for modulating â-amyloid generation and accumulation. The aim of our study was to evaluate the CSF levels of Abeta–42, total-tau (t- tau) and phosphorylated-tau (ptau) in narcoleptic patients, compared with matched healthy controls, to test if the inflammatory pathways in narcolepsy may interfere with CSF Abeta–42 and/or tau metabolisms. Materials and methods Lumbar CSF of patients with narcolepsy and healthy individuals was analyzed by ELISA tests in order to detect the CSF levels of orexin A, Abeta–42, t-tau and ptau proteins. Results We analysed 15 narcoleptic patients and 15 sex and age-matched controls. More than one-and-a-half Abeta–42 CSF levels decrease was detected in narcoleptic patients compared with healthy controls. Moreover in 5 narcoleptic patients (33%) we documented pathological CSF Abeta–42 levels ( 500 pg/ml) and 14 of the 15 narcoleptic subjects (93%) presented CSF Abeta–42 levels lower than the CSF Abeta–42 mean value of the matched controls. Conversely, CSF levels of t- tau and ptau proteins did not statistically differ between groups. Conclusion We hypothesize that the significant decrease of the CSF Abeta–42 levels in narcoleptic patients may support the inflammatory/autoimmune hypothesis at the basis of the pathogenesis of narcolepsy. Therefore, our findings may be particularly appealing since narcolepsy is a neurological disorder caused by possible underlying autoimmune processes, aroused by viral or bacterial infections, responsible for the selective orexinergic neurons loss. In addition, a secondary explanation may be represented by the prevalence of an “amyloidogenic” pathway, due to the deficiency of the alpha-secretase ADAM10, previously described in narcolepsy, which cause the reduction of the CSF Abeta–42 levels in narcoleptic patients. Therefore, further studies are needed to better clarify the pathogenesis of narcolepsy, to understand the role of Abeta–42 and its links with degeneration and loss of the orexinergic neurons. Acknowledgements We thank for their precious help and assistance: N.B. Mercuri, PhD, S. Bernardini, PhD, M. Nuccetelli, MD.