A NEW model-in-a-dish of sporadic Alzheimer's disease, which accounts for more than 90% of Alzheimer's cases and tends to strike people without a family history of the disease, has been created by Harvard University geneticists. The model marks the first time researchers have identified the same molecular abnormalities across multiple sporadic Alzheimer's lines.
The achievement, reported in Cell Reports, removes a major obstacle for scientists seeking to pinpoint the causes of sporadic Alzheimer's and find drugs that might prevent or reverse its devastating neurodegenerative effects. The work also provides insights into early molecular changes that may lead to Alzheimer's and points to a potential treatment target.
Alzheimer's disease affects an estimated 5,700,000 people in the U.S. Until now, most "Alzheimer's in a dish" models have been derived from familial Alzheimer's, a rare form of the disease that runs in families, is caused by dominant genetic mutations, and often manifests before age 65. By contrast, the sporadic form is believed to arise from an array of genetic and environmental risk factors that are not yet fully understood.
The new model "is an intriguing in vitro system that has been missing from the field," says senior study author Bruce Yankner, professor of genetics in the Blavatnik Institute at Harvard Medical School, who, in the 1990s, led the team that first demonstrated the toxic effects of amyloid beta, the hallmark of Alzheimer's.
Using their new model, Yankner and his colleagues identified changes in neural stem cells during early development--including accelerated differentiation and abnormalities in a protein believed to protect against age-related cognitive decline--that may raise the likelihood of developing Alzheimer's later in life. "It's exciting to uncover a shared phenotype. That was unexpected."
The Yankner team began by obtaining skin cells from five people with sporadic Alzheimer's and six healthy people of the same ages. They reverted these adult cells to an earlier, undifferentiated state. Such induced pluripotent stem (iPS) cells can give rise to many other cell types.
At first, the Alzheimer's-derived cells and the controls looked indistinguishable, but when the team coaxed them to mature into neural progenitors--stem cells that give rise to most cell types in the brain--dramatic differences emerged. DNA analyses revealed that the Alzheimer's cells had unusually high activity in genes related to...