HUMAN CORTICAL ORGANOID MODELS REVEAL AN AMYLOID-BETA-INDEPENDENT RESPONSE PHENOTYPE IN EARLY ALZHEIMER’S DISEASE

Alzheimer's disease (AD) is the most common form of dementia in the elderly, which incidence increases drastically with age. Common AD mouse models cannot recapitulate all AD features, which suggest that human specific models are needed to display the full spectrum of the disease. On the other hand, human pluripotent stem cell (hPSC)-derived models present limitations in the stage of maturation and therefore cannot recapitulate disease features. Here, we have generated a long-term 3D human cortical organoid model (LThCO) composed of cortical layer neuronal subtypes and glia cells with temporal acquisition of mature features, similar to the in vivo postnatal brain. Further, LThCOs derived from familial Alzheimer’s disease (FAD) patient cells recapitulate AD hallmarks such as Tau hyperphosphorylation and Amyloid beta aggregation, characterized by an absence of fibrillar or plaque conformation, highlighting an early preclinical-like stage. Interestingly, FAD LThCOs showed reduced lysosomal Cathepsin D (CATD) levels and defects in lysosomal acidification, suggestive of a defective lysosomal function. Lastly, Aβ lowering strategies efficiently restored p-Tau levels but failed to rescue lysosomal defects, highlighting an early AD Aβ-independent response pattern phenotype.
Overall, our work has identified the presence of divergent early AD phenotypes, with Aβ-dependent vs Aβ-independent response phenotypes in human hCO models.
This work shows that FAD LThCOs allow to study the early phases of AD and could be instrumental for the discovery of early new therapeutic targets to combat disease.