Altered molecular mechanism in Alzheimer’s disease and dementia

Our research line is focused in Alzheimer’s disease (AD), but with interest in other neurodegenerative disorders. Translationality of our research lies in we aim to clarify the pathological mechanisms which underlie the disease searching potential diagnostic tools and/or processes with therapeutic relevance. Our group is part of CIBERNED (an ISC-III Center for Networked Biomedical Research focused in neurodegenerative diseases) with members from FISABIO (Foundation for the promotion of health and biomedical research of the Valencian Community) and ISABIAL (Institute of Health and Biomedical Research of Alicante). In recent years, we have been involved in a project of the EU Joint Programming in Neurodegenerative Disease, BIOMARKAPD, an European consortium that aimed to validate classical markers and refine protocols for analysis. Our group is part of the “Society for CSF analysis and clinical neurochemistry”.

Our expertise comprises i) biochemical characterization of PTM for brain/CSF proteins, including glycosylation, phosphorylation, and characterization of proteolytic processing; ii) characterization of ligand-receptor interaction associated to signaling pathways; iii) assessment of sustained inhibition of key enzymes such as cholinesterases and secretases.

Among the recent studies there are: i) β-amyloid (Aβ) and tau hyperphosphorylation (P-tau) cross-talk, role for the reelin protein. Reelin is a signaling protein that modulates synaptic function and plasticity in the brain through interaction with apolipoprotein E receptors. ApoE is the major genetic risk factor for sporadic AD. We demonstrated a novel mechanism by which Aβ regulates reelin expression and glycosylation, thereby influencing its signaling cascade. We also described new apolipoprotein E receptor that influenced amyloid processing.  ii) Interaction and modulation of acetylcholinesterase by P-tau and the role of presenilin 1 in the glycosylation and functional location of acetylcholinesterase. iii) Development of new CSF biomarkers, evaluating the diagnostic potential of particular glycoforms of proteins (including APP), which improve sensitivity and specificity of the biomarkers. We also identify in the CSF several secretases and APP photolytic fragments. We are part of the team involved in the report of the new ADAM10 Tyr167* nonsense mutation in familial AD. More recently, we analyzed different circulating ACE2, the host receptor of SARS-CoV-2 coronavirus, soluble full-length species and proteolytic fragments, as an informative biomarker of the progression of the COVID-19 disease as well as therapy efficacy, including vaccination.