Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia worldwide. With the global number of affected individuals projected to rise from 57 million in 2019 to more than 150 million by 2050, and the economic burden expected to exceed USD 2.8 trillion by 2030, the need for effective therapeutic strategies is urgent. However, progress toward treatment has been hindered by the limited translational value of existing experimental models. Traditional animal models do not adequately recapitulate sporadic AD (sAD), which accounts for over 95% of cases. Two-dimensional induced pluripotent stem cell (iPSC) cultures lack the cytoarchitectural and cellular complexity of the human brain. Consequently, more than 90% of therapeutic candidates successful in preclinical models fail in clinical trials.
Human brain organoids have emerged as a promising alternative, offering a three-dimensional, human-specific model suitable for studying neurodevelopment, neurodegeneration and gene–environment interactions. Patient-derived organoids from familial AD (fAD) can develop hallmark pathological features, yet modelling sAD remains challenging due to subtle genetic drivers, absent vasculature, lack of BBB integrity and partially reset epigenetic landscapes. Recent efforts, such as the BBB-breakdown model introduced by Chen et al., have attempted to induce sAD-like pathology by exposing organoids to serum, mimicking vascular leakage which is an early event in AD progression. Although these systems reproduce multiple aspects of human sAD pathology, no comprehensive molecular validation of these organoid models has been performed. In particular, no study has compared proteomic and phosphoproteomic signatures of sAD patient-derived organoids, induced sAD organoids, and human AD brain tissue. Such validation is essential to evaluate the fidelity and translational value of these models and to establish a reliable platform for drug discovery.
This Seed Fund project aims to fill this critical gap by generating the first comparative proteomic and phosphoproteomic atlas of AD brain organoids, integrating fAD, sAD and BBB-breakdown-induced sAD models. Using established organoid protocols and state-of-the-art mass spectrometry workflows, we will profile total protein abundance and phosphoprotein signatures across these model systems.