Deciphering the Activity of Anti-Alzheimer Drugs – D3AD

Alzheimer’s disease (AD) is a slowly progressing dementia made of two pathophysiological mechanisms - the amyloid and the Tau pathologies – associated with neuroinflammation. Yet, targeting only one mechanism remained elusive to be efficient against AD. Considering the entire pathophysiology of AD as a whole is an alternative therapeutic concept. Recent results show that several of our lead compounds are effective in vivo for restoring memory deficits, repressing the two lesional processes of AD as well as neuroinflammation. The proof of concept is made to show that a single drug can be effective against all pathological hallmarks which together specifically concur with the definition of AD. However important question about the mechanism underpinning the activity of our molecules and identifying the molecular target remains to be addressed. We developed a specific and innovative photoactivable chemical probe derived from our most efficient molecules. A fruitful collaboration between chemists and biologists will tackle our objective through the multiple uses of this multifunctional PAL probe to identify the target, the cellular and in vivo mechanisms using holistic and single-cell transcriptomics, proteomics and imaging approach. Our preliminary data and the control in the synthesis and use of this existing PAL probe together with the expertise of the collaborators warrant the feasibility of this project. Fundamental knowledge about the mechanism at the crossroad between both pathophysiological processes of AD and pathways leading to the curative in vivo effects as well as the identification of the biological targets are achievements for future drug, AD therapeutic as well as the translational valorization to biotech. Deciphering the pharmacological activity is therefore mandatory for future therapeutics of AD as well as related neurodegenerative diseases.