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New Pathway Helps Explain Link Between Stroke and Alzheimer Disease, Providing Target for Therapy



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Investigators identified a pathway by which aberrant p25/cdk5 activity — observed post-stroke — enhances production of the amyloid beta implicated in Alzheimer disease.

Scientists at Columbia University Medical Center have identified a pathway that may explain how the symptoms of stroke trigger Alzheimer disease (AD).

Karen Duff, PhD, a professor in the department of pathology, and her post-doctoral student Yi Wen, PhD, have been working with an enzyme called cdk5 (cyclin dependent kinase 5), which plays many roles in development, including synaptic plasticity.

They reported in the March 13 issue of Neuron that in cell and animal models, levels of the toxic form of amyloid beta (ABeta) that accumulates in the brains of AD patients rise in the presence of an activator of cdk5 called p25, which increases after an ischemic stroke.

Working with a mouse model that overexpresses p25 to enhance cdk5 activity, the investigators observed that the animals show an increase in BACE, or beta secretase, and high levels of ABeta peptide in brain.

The animals do not have any overt cognitive deficits and do not develop tangles, but Dr. Duff contends that this pathway may be important in understanding AD — and how stroke might put people at increased risk. This pathway has been implicated in both conditions, she said.

Dr. Duff and her colleagues also identified a region in the BACE promoter gene responsible for the interaction between p25 and cdk5. The interaction is mediated by another protein, STAT3, which stimulates production of the BACE enzyme, generating ABeta.


DR. KAREN DUFF and colleagues found that inhibiting cdk5 reduced amyloid beta production in mice. The findings suggest that inhibitors of cdk5 could be candidates for therapeutic development.

To confirm their findings, Drs. Wen and Duff lowered the activity of cdk5 through drugs and genetic manipulation (“knockout” mice). They found that attenuation of cdk5 reduced ABeta production in the brain. The investigators used a cdk5 inhibitor from Pfizer that reduced ABeta levels, but long-term use of the drug was toxic so it does not have an immediate clinical application. However, if a similar pathway is implicated in humans, it may be possible to target therapies to that pathway, Dr. Duff said. To Dr. Duff, it is a molecular game of connect-the-dots: p25 levels are increased in neurodegenerative brain tissue, especially after stroke, and cdk5 activity is enhanced in AD brains. Now this connection to STAT3 and BACE adds another piece to the puzzle.


“This paper provides excellent evidence of one mechanism” that could explain the connection between stroke and Alzheimer disease, said James Bibb, PhD, an assistant professor of psychiatry at the University of Texas Southwestern Medical Center in Dallas.

He added that it has been difficult to explain the precise causes of abnormal processing of amyloid precursor protein that produce harmful levels of amyloid beta peptide. Cdk5 could be the missing link. Dr. Bibb suspects that aberrant cdk5 activation is produced by neurons under stress, and in turn it leads to an overproduction of beta secretase by modulating the activity of the transcriptional factor STAT3, which controls secretase gene expression.

“This represents a clear milestone in explaining how this can lead to the demise of neurons in the Alzheimer brain,” said Dr. Bibb. The final experiment — to use cdk5 inhibitors to stop this process — strongly supports its involvement in neurodegeneratve disorders such as AD.

“We still don't know for sure but this is the clearest mechanism we have seen,” he added.

Drs. Duff and Wen, who are part of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the New York State Psychiatric Institute, are now continuing studies using postmortem tissue from patients who died from stroke.