Reelin plasma levels predict cognitive decline in Alcohol Use Disorder: peak levels in patients expressing plasma APOE4 protein

Abstract

Background: Human apolipoprotein (APO)-E4 has been related to neuropsychiatric disorders such as Alzheimer disease and cognitive decline. Reelin and Clusterin share the VLDLR and ApoER2 receptors with APOE4. Here we checked the role of these components in Alcohol Use Disorder (AUD)-induced cognitive decline. Methods: This is a cross-sectional study with AUD-diagnosed patients (DSM-5) (n=24) recruited from an outpatient Alcohol Programme and matched controls (n=34). Participants were assessed by the validated Test of Detection of Cognitive Impairment in Alcoholism (TEDCA). APOE4 presence in plasma (distinguishing APOE4 carriers and no carriers subjects) and its levels were performed by e4Quant technique. The rest of biological markers were tested by Enzyme-Linked Immunosorbent Assay kits. Results: Plasma APOE4 isoform was present in 37.5% and 58.8% of patients and controls, respectively. Quantification analyses revealed that APOE4 reached similar plasma levels in carriers independently if they were AUD subjects or controls. Circulant plasma APOE4 had a negative effect on AUD cognition, specifically affecting Memory/Learning (p<0.01; eta2=0.15). Plasma Clusterin and Reelin increased in patients but, interestingly, Reelin plasma levels peaked in patients expressing APOE4 (p<0.05, lower case Greek eta2=0.09), who showed reduced VLDL and ApoER2 expression in peripheral blood mononuclear cells (PBMCs). Reelin was a good predictor of cognitive loss in patients, accounting for the 42.3% and 54.0% of general intelligence and executive function impairments, respectively. Conclusions: Reelin plasma levels are increased in AUD patients who express the APOE4 isoform, predicting cognitive deterioration to a great extent. Remarkably, plasma Reelin helps to differentiate between AUD patients with and without cognitive decline.

Reelin marks cocaine-activated striatal ensembles, promotes neuronal excitability, and regulates cocaine reward

“…Postnatally, Reelin regulates synaptic function and long-term potentiation in the hippocampus through both post-translational 43,75,76 and transcriptional mechanisms 46 . Additionally, Reelin has links to diverse neuropsychiatric disorders, such as schizophrenia 53,[77][78][79] , substance use disorders 80,81 , and Alzheimer's disease 82,83 . Secreted Reelin protein is cleaved in the extracellular matrix by a variety of metalloproteases 84 , and canonically acts at low-density lipoprotein receptors such as LRP8 (also known as ApoER2) and VLDLR 43 , although non-canonical modes of action have also been identified 85 .…”