Deciphering TDP-43 molecular signatures in LATE: towards a multitarget diagnosis

Dementia in elderly individuals results from a group of devastating diseases that currently affects more than 55 million people worldwide, with Alzheimer’s Disease (AD) being the most common cause of dementia. Recently, LATE (limbic-predominant age-related TDP-43 encephalopathy) was defined as a new disease entity caused by TDP-43 pathology. Importantly, TDP-43 accumulates in up to 75% of AD patients. AD patients with TDP-43 have smaller hippocampal volumes and worsened cognition, suggesting that TDP-43 plays an important role in AD. Additionally, TDP-43 is also a major player in frontotemporal lobar degeneration (FTLD-TDP). Thus, the question arises whether the TDP-43 proteinopathy differs among these diseases. We recently observed distinct patterns of TDP-43 species in AD versus FTLD-TDP cases, however this is not yet known in pure LATE. Therefore, in this project we aim to investigate the differences in TDP-43 aggregate composition, aggregation properties and binding partners across dementing diseases. To address this, I will use human brain samples and state of the art techniques such as spatial proteomics and atomic force microscopy. These findings will have an impact in the clinical stratification of demented patients.