Cerebrospinal Fluid Cyclase-associated protein 2 is increased in Alzheimer’s disease and correlates with tau pathology

Abstract

Background: Synaptic dysfunction is a significant event in Alzheimer’s disease (AD). Cyclase-associated protein 2 (CAP2) plays a role in the modification of spines’ morphology as a result of synaptic plasticity. Previous studies have shown CAP2 alterations in AD models, though its function across the spectrum of AD has not been thoroughly evaluated. Our objectives were to assess whether cerebrospinal fluid (CSF) CAP2 levels are specifically altered in AD compared to other neurodegenerative diseases and whether there is a relationship between CAP2 alteration and amyloid and tau-related biomarkers. Methods: One hundred and ten patients with AD, namely prodromal (n=30) and mild to moderate AD (n=80), as well as 20 individuals with dementia with Lewy bodies (DLB), 20 with frontotemporal dementia (FTD), and 24 healthy controls (HC) underwent a standardized neurological and cognitive-behavioral assessment. Total and phosphorylated tau and Aβ42 levels in CSF were analyzed using Lumipulse, and CAP2 levels were measured using standard ELISA. Between-group differences and correlations among CSF biomarkers were assessed using non-parametric comparisons and partial correlation analyses adjusted for age, sex, and disease duration, respectively. In vitro, neuronal total and phosphorylated Tau were measured by using Western blot analyses in CAP2-downregulated neuronal cell cultures. Results: AD patients (both prodromal and mild-to-moderate stages) showed higher levels of CSF CAP2 in comparison to controls and non-AD patients (p=0.001). In AD patients, CAP2 levels were independent of age, sex and Apolipoprotein-E (APOE) genotype but positively correlated with phosphorylated tau levels. In vitro neuronal cell experiments showed that the reduction of intracellular CAP2 expression correlated with phosphorylated tau levels. Conclusions: CAP2 levels were significantly increased in CSF of AD patients already in prodromal stages. In AD, a correlation between CAP2 and phosporylated tau levels was found both in patients and neuron cellular models. These results further validate the significance of synaptic pathology and its relationship with neuronal dysfunction in AD.