New cell model of most common form of Alzheimer’s points to molecular causes, drug target

New Cell Model Of Most Common Form Of Alzheimer’s Points To Molecular Causes, Drug Target part is one as concers the Health and Medical Updates groups, published immediately upon our scripter Linda Norton upon January 29, 2019, that essay maybe want to search by those tags list Alzheimers, cell, common, drug, form, model, molecular, points, target. We all pleasant to blissful you along with providing these another section reffering health plus I'm always writting the article everyday.


PET scan of a human brain with Alzheimer’s disease. Credit: public domain

Harvard Medical School geneticists have created a new model-in-a-dish of sporadic Alzheimer’s disease, which accounts for more than 90 percent of Alzheimer’s cases and tends to strike people without a family history of the disease.

The model marks the first time researchers have identified the same molecular abnormalities across multiple sporadic Alzheimer’s lines.

The achievement, reported online Jan. 29 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 5.7 million people in the United States. 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,” said senior study author Bruce Yankner, professor of genetics in the Blavatnik Institute at HMS, 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 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,” said Yankner. “That was unexpected.”

Dramatic divergence

Yankner and colleagues 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 neuron differentiation, neuron creation and the formation of connections between neurons.

Those results suggested that the Alzheimer’s progenitor cells would turn into mature neurons far sooner than their healthy counterparts, and indeed, that is what the researchers observed in lab dishes.

“The cells differentiate ‘better,’ or at least faster,” said Yankner. “You get more neurons, not fewer.”

The Alzheimer’s-derived cells also became electrically excitable, or capable of communicating with one another, earlier and more vigorously than the control cells.

What was going on?

Putting questions to REST

Yankner looked for answers in a protein called REST. The protein held special interest for two reasons: because it is known to regulate neural differentiation during early development, and because Yankner had previously shown that, after subsiding in early childhood, REST resurfaces in the aging brain to potentially protect against neurodegeneration and other stresses.

Sure enough, the prematurely differentiating Alzheimer’s cells had less REST in their nuclei than normal cells. The REST that remained did not bind to genes and function normally.

Many sporadic Alzheimer’s cells have misshapen nuclear membranes. Image: Katharina Meyer and King-Hwa Ling/Yankner lab

The researchers also found that the nuclei of the Alzheimer’s cells were more often misshapen and had a higher occurrence of structural changes in their membranes than normal cells. Previous research spotted such defects in the brains of people who died with Alzheimer’s, but how and whether they relate to neurodegeneration has remained unclear.

The researchers wondered whether the constellation of abnormalities—from gene activity to premature differentiation to low REST to defects of the cell nucleus—could be fueled by toxic amyloid beta, the protein famously implicated in Alzheimer’s development. When the researchers shut off production of the amyloid protein, however, nothing changed.

What about phosphorylated tau, the basis of so-called neurofibrillary tangles found in the brains of Alzheimer’s patients? The answer,…

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