New Horizons in Neurodegeneration

A long-term human brain organoid model to unravel human developmental features and early Alzheimer's disease hallmarks

Human brain maturation is a slow process that extends from mid-late embryonic to the adolescent age. This species-specific slow process of maturation is essential for the arising of human specific traits such as increased brain size. 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, common 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 human cortical organoid model (LThCO) to study human brain maturation upon an early postnatal stage, and to model AD in a dish. Our model shows the time-dependent appearance of cortical layer subtypes and glia cells, and increased expression of maturation genes, similar to the in vivo postnatal brain. Further, LThCOs derived from patient familial Alzheimer’s disease (FAD) patient cells showed AD features such as Ab aggregation and Tau hyperphosphorylation. However, they could not recapitulate the presence of Ab fibrils or plaques, corresponding to an earlier preclinical stage. Interestingly, FAD LThCOs lacked axonal transport defects, but showed aberrant decreased lysosomal Cathepsin D. Ab lowering strategies efficiently restored p-Tau levels but failed to rescue Cathepsin D lysosomal defects. These results suggest that lysosomal defects appear at a very early AD stage, and that current therapies aiming to reduce Aβ burden may not be sufficient to rescue these defects in the brain of the patients.