Chronic Traumatic Encephalopathy (CTE) is a unique neuropathological syndrome diagnosed only postmortem but associated with progressive neuromotor and neuropsychiatric symptoms experienced in life. Diagnostic challenges arise from its symptom overlap with more common conditions, and the absence of reliable biomarkers. The formation of insoluble tau inclusions, with the properties of amyloid, is the defining pathology of CTE. However, tau filaments are implicated in more than twenty additional neurodegenerative diseases known as tauopathies and the identification of abnormal tau is only a supportive feature but not definitive for CTE diagnosis.
Electron cryo-microscopy (cryo-EM) studies have resolved atomic structures of tau filaments extracted from the brains of individuals with various tauopathies. These studies have demonstrated that each disease is characterised by a unique tau filament fold (polymorph) conserved among individuals with the same disease. In this project, we are applying conformation‑based detection arrays that aim to discriminate between the multiple tau polymorphs.
This work reports on an in vitro system for recombinantly producing amyloid filaments with polymorphic diversity, including the polymorphs identified in CTE and Alzheimer’s disease (AD). The filaments have been utilised to develop a novel multiplex fluorescent array for distinguishing different tau polymorphs. The aim is to develop structure activity relationship information that leads to the development of probes that can selectively discriminate CTE. In parallel, in situ approaches are being applied to identify probes that might have a read out for CTE, including utilising a unique repository of human CTE lesions that are under the custodianship of the Australian Sports Brain Bank (ASBB). Immunofluorescence staining of sections has been used to refine and validate the discriminating probes. The discovery of a probe or small molecule binder capable of discriminating between tau-polymorphs such as those found in CTE and AD could improve diagnosis and management of CTE during life.