Altered Neural Function in a Human 3D Culture Model of AD
Co-Principal InvestigatorsClifford J. Woolf, PhD Boston Children's Hospital
In this project, we will further develop and characterize a human “Alzheimer’s disease in a dish” model based on a unique three-dimensional (3D) human neural progenitor cell culture technique. In our recent publication and preliminary studies, we have shown that a human 3D cell culture model can recapitulate key events in Alzheimer’s disease (AD), which has not been feasible in AD animal models. Here, we will investigate mechanisms underlying these pathogenic events, including amyloid beta (Aβ), tau tangles, abnormal neuronal activity, synaptic/cellular injury, and potentially, neurodegeneration. If successful, our studies will provide a novel and validated platform for basic mechanistic studies and drug screening in a human brain-like environment, which could largely accelerate AD drug discovery.
We are developing a three-dimensional (3D) human neural cell culture model of Alzheimer’s disease (AD) for basic mechanical studies and drug discovery. Recently, we showed that genetically engineered human neural stem cells combined with a unique 3D culture system we developed, can recapitulate key pathogenic events in AD. Using these 3D human cellular models, we are studying the molecular mechanisms responsible for how β-amyloid (Aβ) accumulation leads to altered neuronal activity, synaptic injuries and eventually neuronal death, in a human brain-like environment. The overarching goal of this study is to establish human cellular AD models that recapitulate the functional deficits caused in patients by Aβ and tau pathologies, for disease modelling and drug discovery.
Key Details. Alzheimer's disease (AD) has become the sixth leading cause of death in the United States, and the number of patients is expected to increase dramatically over the next decade. However, there is no clear therapeutic option at this moment. AD transgenic mice, which have proven very useful for testing candidate AD drugs before human clinical trials, have not been able, however, to fully replicate key parts of the AD pathogenic cascades, including clear tau tangle pathology and neurodegeneration. This might explain why many successful treatments in mice have not led to similar success in humans.
Recently, we produced a novel three-dimensional (3D) human neural cell culture model of AD using genetically engineered human neural stem cells (Choi et al., 2014; Kim et al., 2015). Using this model, we showed, for the first time, that excess accumulation of β-amyloid (Aβ) is sufficient to induce robust tau tangle pathology. While we have successfully recapitulated two major pathological markers of AD, we have not fully characterized the neuronal deficits, including synaptic dysfunction and altered neuronal activity that could contribute to increased vulnerability to neuronal death. Therefore, we will now investigate the presence and degree of altered neural activity in 3D-cultured human neural AD models (Aim 1), and the synaptic/cellular injuries that occur in this model (Aim 2), while exploring the molecular mechanisms underlying neural/synaptic disease phenotypes (Aim 3). The overarching goal of this study is to establish human cellular AD models that closely recapitulate the functional deficits caused in patients by Aβ and tau pathologies, for basic mechanistic studies, disease modelling, and AD drug discovery. Since no AD mouse model of Aβ deposition leads to tangles and neurodegeneration, both of which are critical aspects of the disease, the human neural cell culture model could begin to serve as a disease–relevant drug discovery platform for AD.