Project Portugal 2030

Summary

The project aims to identify and target new molecular mediators in age- and AD-associated mitochondrial dysfunction, thus developing a drug delivery system prototype to promote retinoic acid receptor (RAR) signalling. The main goal is to rescue age-associated mitochondria homeostasis disruption, promote healthy ageing, and restore cognitive function in the context of Alzheimer’s Disease. To do so, it is divided in a series of sequential objectives: Objective 1: Elucidate the impact of mitochondria homeostasis (mitostasis) in healthy and pathological ageing (Activity 1 - Age neurons and modulate mitostasis) Firstly, we will elucidate the impact of mitochondria homeostasis (mitostasis) in ageing, to clarify how it differentiates healthy to pathological ageing Objective 2: Rescue metabolic dysfunction (Activity 2 -– Activate RAR signalling to rescue ageing mitostasis) Objective 3: develop a therapeutic option for ageing-associated mitostasis disruption (Activity 3 - Develop and optimise a nano-system for neuronal drug delivery) Following, we will rescue this mitostasis disruption, by modulating RAR signalling. This process will clarify the specific RAR-isoforms involved, which will be encapsulated in a nano-system for neuronal drug delivery. Objective 4: Promote in vitro mitostasis in ageing and AD (activity 4 –Rescue metabolic dysfunction with drug delivery system and activity 5 - Deploy drug delivery system across BBB model to promote Abeta clearance) This drug delivery system will be used to rescue neuronal mitostasis dysfunction in vitro, in ageing and AD; following, its capacity to cross the blood brain barrier (BBB) will be assessed using an in vitro model, which will also be used to evaluate its effect on astrocytic clearance of Abeta. Objective 5 – Rescue cognitive dysfunction in vivo (Activity 6 – Improve cognitive function in AD animal model) In a final objective, the aim is to explore this technology in a physiologically significant manner, by using the nano-system to promote mitostasis in vivo, using an animal model of dementia, aiming to rescue cognitive dysfunction. Although not anticipated as a direct outcome of this action, the overall goal to develop a new therapeutic option that can be translated to clinic; to that end, the team is coordinating with the University’s Technology Transfer Office to ensure that publication and dissemination activities do not jeopardise intellectual property protection.