NIA-supported researchers recently developed an innovative method to culture human brain cells in the laboratory and then modeled, for the first time, the cascade of cellular changes involved in the onset and progression of Alzheimer’s disease. The findings support the “amyloid hypothesis,” a 30-year-old theory that the build-up of beta-amyloid protein in the brain kick starts the toxic changes that lead to tau tangles, and ultimately, cell death. The results by researchers at Massachusetts General Hospital (MGH), Boston, were published online Oct. 12 in Nature.
Drs. Rudolph Tanzi and Doo Yeon Kim of MGH’s Genetics and Aging Research Unit developed a petri-dish model that is three-dimensional and gelatinous—an environment that more closely resembles neurons in the living brain than the standard tissue culture methods. The investigators grew human neural stem cells carrying variants of two genes, amyloid precursor protein and presenilin 1, to develop cultured neurons similar to brain cells in people with early-onset, familial Alzheimer’s disease.
After 6 weeks in the culture dish, the researchers performed a series of tests that replicated, for the first time in a laboratory, the sequence of events associated with early-onset familial Alzheimer’s pathology in the human brain. Treatment with beta- and gamma-secretase inhibitors dramatically decreased beta-amyloid deposits and tau levels in the cells, offering further evidence in support of the amyloid hypothesis. The findings also provide insight into other questions, such as whether toxic tau tangles are caused directly by beta-amyloid accumulation or form independently.
Unlike previous studies using mouse and other models, the new culture system appears to have allowed the formation of both beta-amyloid plaques and tau tangles. Because the new system is less costly and takes less time to screen promising drugs than animal models, the researchers expect it will speed drug development in Alzheimer’s disease and other neurological disorders.
Reference: Choi SH, et al. A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature published online Oct 12, 2014.doi: 10.1038/nature13800