This peptide blocks a hyperactive brain enzyme that contributes to the neurodegeneration seen in Alzheimer’s disease and other diseases.

When researchers treated mice with a peptide that blocks a hyperactive form of an enzyme called CDK5, they found a dramatic reduction in neurodegeneration and DNA damage in the brain. These mice also showed improved ability to perform tasks such as learning to navigate a water maze.

“We found the effects of this peptide to be amazing,” says Li-Huei Tsai, director of the Massachusetts Institute of Technology Picower Learning and Memory Institute and senior author of the study. “We have seen excellent results in terms of reducing neurodegeneration and neuroinflammatory responses, as well as relieving behavioral disorders.”

With further trials, researchers hope that the peptide could eventually be used to treat patients with Alzheimer’s disease and other forms of dementia with overactivation of CDK5. This peptide does not interfere with CDK1, an essential enzyme that is structurally similar to CDK5, and is similar in size to other peptide drugs used in clinical applications.

Ping-Chieh Pao, a research scientist at the Picower Institute and lead author of the paper, said this week that Proceedings of the National Academy of Sciences.

Target CDK5

Early in her career, Tsai has studied the role of CDK5 in Alzheimer’s disease and other neurodegenerative diseases. As a postdoctoral fellow, he identified and cloned her CDK5 gene, which encodes a class of enzymes known as cyclin-dependent kinases. Most of the other cyclin-dependent kinases are involved in regulating cell division, but CDK5 is not. Instead, it plays an important role in the development of the central nervous system and also helps regulate synaptic function.

CDK5 is activated by a smaller protein known as P35 with which it interacts. When P35 binds to CDK5, the conformation of the enzyme changes, allowing it to phosphorylate (add a phosphate molecule to) the target. However, in Alzheimer’s disease and other neurodegenerative diseases, P35 is cleaved into a small protein called P25. It can also bind CDK5, but with a longer half-life than P35.

Upon binding to P25, CDK5 becomes more active inside the cell. P25 also allows CDK5 to phosphorylate molecules other than its usual targets, including the tau protein. Hyperphosphorylated tau protein forms neurofibrillary tangles, one of the hallmarks of Alzheimer’s disease.

In a previous study, Tsai’s lab showed that transgenic mice engineered to express P25 develop severe neurodegeneration. In humans, P25 is associated with several diseases, not only Alzheimer’s disease, but also Parkinson’s disease and frontotemporal dementia.

Pharmaceutical companies have attempted to target P25 with small molecule drugs, but these drugs also interfere with other cyclin-dependent kinases, tend to cause side effects, and none have been tested in patients.

The MIT team decided to take a different approach to targeting P25 by using peptides instead of small molecules. They designed a peptide with a sequence identical to that of a segment of CDK5 known as the T-loop, a structure critical for CDK5’s binding to his P25. The entire peptide is only 12 amino acids long, slightly longer than most existing peptide drugs that are 5-10 amino acids long.

“From a peptide drug perspective, smaller is usually better,” Tsai said. “Our peptides are close to their ideal molecular size.”

dramatic effect

In testing neurons grown in laboratory dishes, the researchers found that treatment with the peptide led to a modest decrease in CDK5 activity. These tests also showed that the peptides did not inhibit normal CDK5-P35 complexes and did not affect other cyclin-dependent kinases.

The researchers tested the peptide in a mouse model of Alzheimer’s disease in which CDK5 is overactive and found a myriad of beneficial effects, including reduced DNA damage, neuroinflammation and neuronal loss. These effects were more pronounced in studies in mice than in studies in cultured cells.

Peptide treatment also led to dramatic improvements in another mouse model of Alzheimer’s disease with a mutant form of the tau protein that causes neurofibrillary tangles. showed a decrease in both In addition to these effects in the brain, researchers also observed behavioral improvements. Peptide-treated mice were treated with a control peptide (a scrambled version of the peptide used to inhibit CDK5-P25) in a task that required learning to navigate a spatial memory-dependent water maze. It performed much better than the mouse that was tested.

In studies of these mice, researchers injected peptides and found that they could cross the blood-brain barrier and reach neurons in the hippocampus and other parts of the brain.

The researchers also analyzed changes in gene expression that occur in mouse neurons after treatment with peptides. Among the changes they observed was increased expression of about 20 genes that are normally activated by a family of gene regulators called MEF2. Tsai’s lab had previously shown that her MEF2 activation of these genes could confer brain resilience to cognitive deficits in people with tau tangles, and she said peptide treatment had similar effects. We hypothesize that it may lead to

Tsai now plans to do further research in other mouse models of diseases involving P25-related neurodegeneration, including frontotemporal dementia, HIV-induced dementia, and diabetes-related cognitive impairment.

“It’s very difficult to say exactly which diseases will benefit most, so I think more research is needed,” she says.

This study was funded by the National Institutes of Health.