Project R-11616

The role of APOE in Tau-pathology and neurodegeneration downstream of Aβ pathology: Exploiting a human protective APOE3 (R136S) mutation to develop novel therapeutic strategies for Alzheimer's disease (Research)

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder imposing an unbearable socioeconomic burden worldwide. Current treatment approaches fail to halt AD progression, indicating the need for new therapeutic strategies and more complete AD preclinical models, the focus of this project. This project is inspired by the identification of a protective APOE3 (R136S) Christchurch (AE3ch) mutation in an individual with genetic AD (PS1 mutation carrier). Strikingly, the AE3ch mutation delayed clinical symptoms along with tau-pathology for about 30 years despite high amyloid load (Nature Med, 2019). This case thereby points to disease modifying potential of ApoE dependent processes in humans even in severe ADAD carriers. Understanding the protective mechanism of this case and this APOE3ch mutation holds the key to new avenues for therapies in AD. Hereto, we investigate the role of ApoE and ApoE3ch in amyloid-mediated Tau pathology and subsequent Tau-driven neurodegeneration in in vitro and in vivo models. We anticipate that characterization of this APOE driven anti-AD pathway within neuroinflammatory context, is key to innovative insights in AD pathogenesis, opening new avenues for AD-modifying therapies.

01 January 2021 - 31 December 2023