Characterization of a transgenic human brain organoid model to study Alzheimer’s disease

Alzheimer's disease (AD), the most frequent cause of dementia in the elderly, is characterized by the presence in the brain of amyloid beta (Aβ) plaques and neurofibrillary tangles composed of hyper-phosphorylated Tau. A minority of patients are affected by familial AD (FAD), also called early onset AD (EOAD), caused by inherited autosomal dominant mutations. In this project, we study AD pheno-types using a transgenic human FAD brain organoid (BO) model that carries the expression of the amyloid precursor protein (APP) bearing two mutations from FAD families, and a SAD-like model through exposure of wild-type BOs to an external source of Aβ to study the effects on cell identity and neuronal function. Our results show that human transgenic FAD BOs produce high levels of Aβ and recapitulate the presence of pathological hyperphosphorylated Tau. Interestingly, human transgenic FAD and SAD-like BOs show early alterations in the expression of layer subtype cortical neuronal and glial genes, suggesting early effects on cell identity or neuronal de-differentiation and late neuronal functional defects. These results suggest that transgenic FAD and SAD-like BO models can recapitulate the presence of major AD hallmarks, and that these models could be instrumental to identify early mechanisms of disease in AD.