Structural bases of the ADAM10 isoforms proteolytic activity

• Grant number: 23/00868-2
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: October 01, 2023
• Status: Discontinued
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Márcia Regina Cominetti
• Grantee: Sabrina Dorta de Oliveira
• Host Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
• Associated research grant: 21/01863-9 - Biology and function of ADAM10 isoforms for differential diagnosis of Alzheimer's Disease by electrochemical sensors, AP.TEM
• Associated scholarship(s): 24/13949-3 - Proteins Involved in ADAM10 Cleavage from the Plasma Membrane: Investigation Using Molecular Bioengineering Strategies, BE.EP.DR

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease resulting from neuronal loss and abnormal extra and intracellular fibrillar deposits formed by senile plaques and neurofibrillary tangles, respectively. Senile plaques originate from the accumulation and aggregation of the beta-amyloid peptide. At the same time, neurofibrillary tangles result from hyperphosphorylation of the tau protein present in the microtubules of neuronal axons. To avoid the formation of senile plaques, it is necessary that the processing of the amyloid precursor protein (APP) be carried out sequentially by alfa and gamma-secretases (non-amyloidogenic route). The main alfa-secretase involved in this process is the disintegrin and metalloproteinase 10 (ADAM10). ADAM10 is a peripheral biomarker that can contribute to understanding the still unknown aspects of AD and an early diagnosis using less invasive and low-cost methods. The LABEN group identified that soluble isoforms of ADAM10 in plasma and cerebrospinal fluid (CSF) in patients with AD are in higher concentrations.  This led the group to investigate the hypothesis inactivity of the isoforms and your possible relation to the self-inhibition mechanism of the extracellular domain. This hypothesis evaluation through the study of the activity of these isoforms in the presence of a modulating antibody (8C7). That research will contribute to both the understanding of the biological mechanisms involved in the formation of senile beta-amyloid plaques as well as the evaluation of the effect of possible drugs that allow the reactivation of isoforms by conformational modulation.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DORTA, SABRINA; ALEXANDRE-SILVA, VANESSA; POPOLIN, CECILIA PATRICIA; DE SOUSA, DANILO BARROSO; GRIGOLI, MARINA MANTELLATTO; PELEGRINI, LUCAS NOGUEIRA DE CARVALHO; MANZINE, PATRICIA REGINA; CAMINS, ANTONI; MARCELLO, ELENA; ENDRES, KRISTINA; et al. ADAM10 isoforms: Optimizing usage of antibodies based on protein regulation, structural features, biological activity and clinical relevance to Alzheimer's ' s disease. AGEING RESEARCH REVIEWS, v. 101, p. 18-pg., 2024-09-12. (23/00449-0, 23/00868-2, 21/01863-9, 21/14673-3, 22/15314-0)