A team led by Dr. Laurent Roybon at Lund University has recently published an article in Stem Cell Reports, outlining the development and validation of an innovative platform to study hippocampal dysfunction in Alzheimer’s disease (AD).
The hippocampus is one of the first regions in the brain to be affected during the development of AD, undergoing degenerative changes that lead to loss of memory. However, studying the molecular pathways that cause these changes in the hippocampus is complicated by limited tissue availability. A further problem is the fact that mouse models of AD do not always recapitulate the human disease. Induced pluripotent stem cells (iPSC), created using skin cells donated by people with AD, offer a potential solution to these problems, enabling researchers to study the molecular causes of AD in the human context.
In their paper, Dr. Roybon and colleagues describe the methodology for creating 3D spheroids of hippocampal cells, using skin cells from two patients with different types of genetic AD as their starting material. This involved a form of molecular time-travel, first turning back the clock to an early developmental stage (creating iPSC) then fast-forwarding them into hippocampal cells. These cells were grown in a 3D matrix, rapidly creating hippocampal spheroids from patients with AD.
A series ofin vivoandin vitrotests showed that the hippocampal spheroids retained many of the features of AD, including increased ratios of pathogenic amyloid-beta proteins and the presence of synaptic pathology. Interestingly, the protein composition of the hippocampal spheroids differed according to the type of genetic AD of the original skin cell donor. Finally, the researchers were able to use gene therapy to alter the gene expression programme of the hippocampal spheroids, promoting the expression of genes involved in synaptic transmission.