MODELING ALZHEIMER’S DISEASE WITH HUMAN CEREBRAL ORGANOIDS: RECAPITULATING PATHOLOGY AND PROTEOMIC BIOMARKERS

Alzheimer’s disease (AD) is histopathologically characterized by the accumulation of neurofibrillary tangles and amyloid plaques in the brain, driven by hyperphosphorylated Tau (p-Tau) and β-amyloid peptide (Aβ), respectively. Traditional in vivo and in vitro research models often fail to capture the complexity of the human brain or the early stages of AD. To address this, we utilized three-dimensional human cerebral organoids (hCOs) generated from human induced pluripotent stem cells (hiPSCs) to model familial AD (fAD).
In this study, we generated, using the protocol established in our laboratory, and characterized hCOs derived from hiPSCs carrying familial AD (fAD) mutations (PSEN1^G206D and APP duplication), compared them to controls.
Using immunohistochemistry and RT-qPCR, we monitorized the progression of the AD phenotype in hCOs. Furthermore, we performed proteomic analysis to identify disease-relevant signatures. Our results demonstrate a significant increase in p-Tau levels, and a elevated Aβ42/40 ratio in AD hCOs compared to controls. Proteomic profiling revealed the presence of proteins currently used as clinical biomarkers, alongside specific alterations in pathways associated with neuron damage, neuroinflammation, oxidative stress or APP processing.
In conclusion, hCOs carrying fAD mutations successfully recapitulate key histopathological and proteomic features of AD. These models represent a valuable platform for elucidating disease mechanisms and screening potential therapeutic compounds in a human-relevant context.