Alzheimer’s Disease (AD) is caused by the progressive death of brain cells (neurons) leading to symptoms such as memory loss and confusion. In order to develop new treatments for AD, it is important to have laboratory-based models of the disease in order to further understand the causes of AD and to test new potential therapeutics.
The team led by Dr Selina Wray at UCL have generated stem cells and neurons from patients with dementia that have a faulty copy of a gene called tau, which is thought to play a role in dementia. These neurons therefore produce abnormal tau similar to what is seen in AD, allowing comparison of their function to neurons grown from people who do not have dementia. Initial studies revealed that the neurons from dementia patients maintain the abnormal tau associated with the disease and that when cultured in specialized microfluidics devices, the functional connections between neurons obtained from healthy patients can be studied.
Building on these initial findings, the team will determine whether connections between neurons are disrupted when they have abnormal tau. They will also test the ideas that abnormal tau leads to dysfunctional mitochondria (which supply cells with energy), and that abnormal tau can spread between neurons, making other neurons either dysfunctional or causing them to die. The development of these assays and novel devices will allow them to be used as a platform for drug screening in the future.
Full details about this CRACK IT Challenge can be found on the CRACK IT website.
Esposito T et al. (2015). Developmental regulation of tau splicing is disrupted in stem cell-derived neurons from frontotemporal dementia patients with the 10 + 16 splice-site mutation in MAPT. Human Molecular Genetics, 24(18):5260-9. doi:10.1093/hmg/ddv246.
Esteras N et al. (2017). Mitochondrial hyperpolarization in iPSC-derived neurons from patients of FTDP-17 with 10+16 MAPT mutation leads to oxidative stress and neurodegeneration. Redox Biology, 12: 410–422. doi: 10.1016/j.redox.2017.03.008.
Contractor(s)Dr Selina Wray
University College London
Sponsor(s)Alzheimer's Research UK