APP-mediated regulation of autophagic flux for Down syndrome therapy

Overview

This research focuses on understanding the genetic mechanisms underpinning autophagic dysfunction in Down syndrome (DS), with an emphasis on the APP-Rab5 axis. Dysregulation of autophagy, a process crucial for cellular health, is linked to neurodegenerative diseases, including Alzheimer's disease (AD) and is prevalent in DS. By investigating the role of increased APP gene dosage leading to Rab5 hyperactivation, this study aims to elucidate how this affects the endolysosomal network and reduces autophagic flux, contributing to neurodegeneration in DS.

Technical specifications

The research hypothesizes that increased APP gene dosage in DS leads to Rab5 hyperactivation, causing widespread dysregulation of the endolysosomal network. This includes hyperactivation of Rab7, Rab11, Rab4, and elevated levels of lysosomal cathepsins such as cathepsin B, L, and D. The study will conduct comparisons between the DS Dp16 mouse model and human samples to assess autophagy pathway changes. Additionally, mechanisms linking APP gene dosage to mTOR hyperactivation will be explored, hypothesizing a reduction in the TSC complex, activation of Rheb and mTOR, and subsequent reduction in autophagic flux. Therapeutic potential is being tested using App-ASO and Rab5-ASO in mouse models to rectify autophagic dysregulation.

Technology readiness level

Currently at TRL 5, the research has moved beyond proof of concept, having validated the efficacy of ASOs in mouse models. Further validation is planned to ensure the findings' consistency between animal models and human samples, aiming to develop potential therapeutic interventions for DS-related neurodegenerative conditions.