A pair of studies published recently report the creation of new “disease-in-a-dish” models of Alzheimer’s disease, the sixth-leading cause of death in the United States. The studies were published by two groups, both supported in part by NIA, and both using human-derived induced pluripotent stem cells (iPSCs) to create models that realistically mimic Alzheimer’s disease, providing a new avenue for studying the cellular mechanisms underlying Alzheimer’s and the development of potential treatment strategies.
The first model is described in a study published in Neuron and was developed by a research team led by scientists at Harvard’s Brigham and Women’s Hospital. The second, from a team led by scientists at the Beckman Research Institute of City of Hope in Duarte, California, was published in Advanced Science.
In the first study, the Brigham team created a repository of iPSC lines derived from frozen blood cells collected from 53 people, now deceased, who took part in the Religious Order Study or the Memory and Aging Project (MAP). Sixteen of these people had been diagnosed with Alzheimer’s and Alzheimer’s dementia. Autopsies confirmed the presence of amyloid plaques and tau tangles, which are two hallmarks of Alzheimer’s disease. About one-third of the participants had neither the diagnoses nor physical evidence of disease in their brains. The other third had a build-up of amyloid plaques but showed no cognitive impairment prior to their deaths.
Scientists reprogrammed the frozen cells into functional neurons. The team performed RNA and proteomic analyses on these cells and on cells taken from postmortem brain samples from the same group of participants. The scientists found that the iPSC-derived neurons reflected the donors’ levels of plaque and tangle build-up, and disease state at the time of death.
The team also identified and validated protein phosphatase 1, or PP1, which plays an important role in certain neuronal functions, as a molecular link between the genetic risk factor for late-onset Alzheimer’s disease and amyloid plaques and tau tangles.
In the second study, the Beckman team used iPSCs derived from human fibroblast, or skin, cells to create 3D clusters, or brain organoids. These clusters are exposed to different conditions and chemicals in the lab that induce the formation of different layers of cells that resemble the layers seen in a normal human brain.
One of the challenges with studying Alzheimer’s disease in iPSC-derived brain cells is that these cells are essentially young cells. In this study, scientists showed they could have the organoids mimic Alzheimer’s-like pathology by exposing them to blood serum. Breakdown of the blood-brain barrier, which may allow leakage of serum and other blood factors into the brain, is a known risk factor for Alzheimer’s. The Beckman research team found that organoids exposed to serum developed plaques and tangles similar to that seen in the Brigham study. Serum exposure also reduced neuron activity in the organoids.
The first study used only neurons. Future studies will involve inducing the other brain cell types that are involved in Alzheimer’s pathology. Likewise, scientists working with brain organoids will continue to improve these models to more closely mimic the structure and physiology of the human brain. Still, these studies provide two new platforms for identifying and validating the molecular mechanisms underlying Alzheimer’s and providing potential new avenues for developing effective treatments.
The research at Brigham and Women’s Hospital was supported in part by NIA grants P30AG10161, R01AG15819, R01AG017917, R01AG30146, R01AG36836, U01AG32984, and U01AG46152. The research at the Beckman Research Institute of City of Hope was supported in part by NIA grants RO1AG056305, RF1AG061794, R56AG061171, P30AG019610, RF1DA048813, RO1AG056303, and P30AG066519.
Chen X, et al. Modeling sporadic Alzheimer’s disease in human brain organoids under serum exposure. Advanced Science. 2021;e2101462. ePub Aug. 2. doi: 10.1002/advs.202101462.
Lagomarsino VN, et al. Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors. Neuron. 2021. ePub Sept. 2. doi: 10.1016/j.neuron.2021.08.003.