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 a sporadic form of the disease (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 transgenic FAD and FAD hiPSC-derived hBOs produce high levels of Aβ peptides and recapitulate the presence of small Aβ aggregates. Interestingly, FAD and SAD-like hBOs don’t show any major impact on apoptotic processes but display alterations in the expression of layer subtype cortical neuronal and glial genes that suggest 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.