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. A minority of patients are affected by familial AD (FAD), caused by inherited autosomal dominant mutations while most patients suffer from sporadic AD (SAD), favored by genetic and environmental factors.

In this project, we aim to unravel early AD phenotypes using FAD like human brain organoid (hBO) models derived from either transgenic FAD pluripotent stem cells (hPSCs APP Swedish and London) or induced pluripotent stem cells (hiPSCs) derived from FAD patient cells (hiPSCs APP London); and a third SAD-like model generated through exposure of wild-type hBOs to an external source of Aβ. Our results show that human FAD and SAD-like hBOs show the presence of Aβ aggregates, which further accumulate upon time in culture. Early FAD and SAD-like hBO models do not show Tau pathology but present alterations in the expression of layer subtype cortical neuronal and glial genes. Interestingly, FAD and SAD-like hBOs do not undergo major apoptotic processes, neither changes in proliferation or neurogenesis, which suggests early effects on cell identity or neuronal de differentiation.

These observations suggest that AD human brain organoid models could be a reliable and instrumental tool to identify early mechanisms of AD pathogenesis.