Development of an immunoassay for detection of truncated tau by caspase 6

• Grant number: 22/10299-2
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: January 09, 2023
• End date: January 08, 2024
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Marcio Luiz Figueredo Balthazar
• Grantee: Liara Rizzi
• Supervisor: Lea Tenenholz Grinberg
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: University of California, San Francisco (UCSF), United States
• Associated to the scholarship: 19/23028-4 - Characterization of individuals with suspected non-Alzheimer pathophysiology (SNAP) through multimodal biomarkers, BP.PD

Abstract

The goal of this proposal is to develop a CSF assay to detect N-terminal caspase-6 (Casp6)-truncated tau (tr-tau) and measure levels of this biomarker in Alzheimer's disease (AD) and other tauopathies. Neurofibrillary tangles (NFT), formed by the intraneuronal deposition of tau, are one of the pathological hallmarks of AD. The mechanisms involved in the early pathological processing of tau until the aggregation into NFT progress through sequential changes that may comprise abnormal phosphorylation, conformational changes, and truncation. Tau protein can be cleaved by cysteine-aspartic proteases called caspases. Tr-tau by caspases leads to the development of insoluble and toxic fragments prone to self-aggregation. Casp6 may have a critical role in AD, cleaving tau protein mainly after certain aspartic acid (D) residues: D421, D13, and D402. Although the percentage of neuronal phosphorylated tau (p-tau) and tr-tau in AD is known to be similar, the overlap is about 40%, showing that an important pathological factor has been overlooked. Since the total burden of tau cannot be explained only by p-tau levels, identifying tr-tau contributions to AD, may be of value to understand its pathophysiology and therapeutic development. The development of biomarkers for tr-tau is an unmet field in AD research. Hence, this research project aims to develop an immunoassay to detect tr-tau cleaved by Casp6 at the D13 site in AD. In addition, the presence and co-occurrence of tr-tau and p-tau will be tested in biofluids of AD patients. (AU)