CSF-ApoER2 fragments as a read-out of reelin signaling: Distinct patterns in sporadic and autosomal-dominant Alzheimer disease

Reelin is a glycoprotein associated with synaptic plasticity and neurotransmission. The malfunctioning of reelin signaling in the brain is likely to contribute to the pathogenesis of Alzheimer's disease (AD). Reelin binding to Apolipoprotein E receptor 2 (ApoER2) activates downstream signaling and induces the proteolytic cleavage of ApoER2, resulting in the generation of soluble fragments. To evaluate the efficiency of reelin signaling in AD, we have quantified the levels of reelin and soluble ectodomain fragments of ApoER2 (ectoApoER2) in the cerebrospinal fluid (CSF). CSF from sporadic AD patients (sAD; n = 14, age 54–83 years) had lower levels of ecto-ApoER2 (~31% reduction; p = .005) compared to those in the age-matched controls (n = 10, age 61–80), and a higher reelin/ecto-ApoER2 ratio. In contrast, autosomal dominant AD patients, carriers of PSEN1 mutations (ADAD; n = 7, age 31–49 years) had higher ecto-ApoER2 levels (~109% increment; p = .001) and a lower reelin/ecto-ApoER2 ratio than the non-mutation carriers from the same families (n = 7, age 25–47 years). Our data suggest that the levels of ecto-ApoER2 in CSF could be a suitable read-out of an impaired reelin signaling in AD, but also indicate differences between sAD and ADAD.This study was funded in part by the EU BIOMARKAPD-Joint Programming on Neurodegenerative Diseases (JPND) project, by the Instituto de Salud Carlos III (ISCIII grants PI11/03026 and PI15/00665 to JSV, PI08/0036 and PI12/00013 to RSV, and PI11/03023 to JLM), by the Direcció General d'Universitat, Investigació i Ciència, GVA (AICO/2018/090 to JSV), co-financed by the Fondo Europeo de Desarrollo Regional (FEDER, “Investing in your future”), and through CIBERNED, ISCIII.Peer reviewe