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Medicineworld.org: Alzheimer's disease as a case of brake failure?

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Alzheimer's disease as a case of brake failure?




Rutgers researcher Karl Herrup and his colleagues at Case Western Reserve University have discovered that a protein that suppresses cell division in brain cells effectively "puts the brakes" on the dementia that comes with Alzheimer's disease (AD). When the brakes fail, dementia results.

This discovery could open the door to new ways of treating Alzheimer's disease, which affects up to half the population over the age of 85.

Determining the proteins previously unsuspected role in AD is an important piece of the puzzle and it brings a new perspective to the basis of AD. It changes the logic from a search for a trigger that kicks off the dementia to the failure of a safety that has suppressed it, said Herrup, chair of the Department of Cell Biology and Neuroscience at Rutgers, The State University of New Jersey.



Alzheimer's disease as a case of brake failure?
In a human brain tissue sample with Alzheimer's disease, the brown Cdk5 is in the nucleus of the five cells in the upper center. In the three cells (arrows) with red nuclei, the brown Cdk5 is just outside the nucleus. The red means that the neuron is trying to divide and is hence on its way to die.

Credit: Karl Herrup, Rutgers University


The scientists reported their findings in the in the June 24 Proceedings of the National Academy of Sciences (PNAS). The paper was previously available online in the PNAS Early Edition.

Herrup has spent a good part of his career seeking to unravel the mystery behind unrestrained cell cycling. Looking at AD through the lens of cancer, Herrup sees the rampant cell division linked to cancer mirrored in AD-related dementia.

In cancer, the seemingly uncontrollable cell division enables the disease to overwhelm normal body cells. Adult neurons, or nerve cells, don't normally divide. (Malignant brain tumors do not grow from neurons but from glial cells.) Instead of producing new neurons in the brain, the cycling leads to cell death, which causes progressive dementia.

"Every cell wants to divide, and that basic urge never leaves the cell," Herrup said.

"Homeostasis in the brain has worked out a way to successfully suppress cell cycling, but with age even that highly successful program sometimes fails, resulting in a catastrophic loss of neurons".

Herrup's team experimented with a protein family known as cyclin-dependent kinases (Cdk). These enzymes power the cell cycle, driving it forward through its various phases. The researchers focused on one particular kinase Cdk5 termed "an atypical kinase" because they could find no involvement in propelling the cell cycle. They observed that while it appears to be inert as a cell cycle promoter, Cdk5 in the nervous system actually functions to hold the cell cycle in check.

"Its mere presence helps protect the brain," Herrup said. "What we discovered is that Cdk5 acts as a brake, not a driver".

Their latest laboratory research examined the workings of Cdk5 in human AD tissues and in a mouse model. Normally, the protein resides in the nerve cell nucleus, but in the presence of AD both in the mouse model and in the human tissue the disease process drives the protein out into the cell's cytoplasm. This disrupts the status quo, overrides the brake and unleashes a chain of events that ultimately leads to the death of the cells and the resulting dementia.

"The ejection of Cdk5 out of the nucleus is probably correlation to the changed chemistry of the Alzheimer's brain and chronic inflammation that accompanies AD," Herrup said.


Posted by: Daniel    Source




Did you know?
Rutgers researcher Karl Herrup and his colleagues at Case Western Reserve University have discovered that a protein that suppresses cell division in brain cells effectively "puts the brakes" on the dementia that comes with Alzheimer's disease (AD). When the brakes fail, dementia results.

Medicineworld.org: Alzheimer's disease as a case of brake failure?

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