Methods and Compositions for Tauopathy Diagnosis and Treatment

Specific cleavage characteristics of Tau seed competence associated with stress and inflammation in neurons in Alzheimer’s disease.

Background

The monomeric Tau is a soluble cytosolic protein that can aggregate under pathological conditions to form highly organized, disease-specific filament structures. The Tau isoforms and their post-translational modifications are linked to both Alzheimer’s disease and frontotemporal dementia. Knowledge of human Tau is important for the development of diagnostics and therapeutic agents. For example, the knowledge of the pattern of Tau post-translational modifications on the pathologic species would allow improvement of the PET reagent affinities for Tau, hence providing an early-stage diagnosis. Defining the chemistry of the pathologic Tau proteoforms during the progression of the disease would allow targeting of specific epitopes using therapeutic antibodies or small molecules at every stage of the disease.

Technology Overview

At Boston Children’s Hospital, a research group worked to identify specific cleavage characteristics of Tau seed competence. The investigators associated the proteolytic cleavage of Tau with stress and inflammation in neurons in Alzheimer’s disease using a cell model. Hence, for the first time, the researchers were able to provide insight into the mechanism by which stressors and environmental risk factors produce Tau species capable of initiating aggregation through the activation of inflammatory pathways.

Benefits

• Ability to develop a specific PET radiotracer for an accurate, early-stage diagnosis
• Opportunity to develop specific antibodies and inhibitors to all the cytokines to prevent the spread and progression of the disease

Applications

• Diagnosis and treatment of Alzheimer’s disease and frontotemporal dementia

Further Details:

Wesseling, Hendrik et al. “Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer's Disease.” Cell vol. 183,6 (2020): 1699-1713.e13. doi:10.1016/j.cell.2020.10.029