New Peptide Could Unlock Alzheimer’s Disease Treatment

MIT neuroscientists discovered a mechanism to reverse neurodegeneration and other symptoms of Alzheimer’s disease by interfering with an enzyme that is generally overactive in Alzheimer’s patient’s brains.
The researchers discovered huge decreases in neurodegeneration and DNA damage in the brain after treating mice with a peptide that suppresses the overactive version of an enzyme called CDK5. These mice also demonstrated gains in their ability to learn to navigate a water labyrinth.

“We found that the effect of this peptide is just remarkable,” says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and the senior author of the study. “We saw wonderful effects in terms of reducing neurodegeneration and neuroinflammatory responses, and even rescuing behavior deficits.”

The researchers anticipate that further testing will lead to the peptide being utilized as an Alzheimer’s Disease treatment and as a treatment for other kinds of dementia who have CDK5 overactivation. The peptide has the same size as other peptide medicines used in clinical applications and does not interact with CDK1, an essential enzyme that is structurally similar to CDK5.

Ping-Chieh Pao, a Picower Institute Research Scientist, is the lead author of the paper, which was published this week in the Proceedings of the National Academy of Sciences.

Tsai has been researching the role of CDK5 in Alzheimer’s disease and other neurodegenerative disorders since her early career. As a postdoc, she discovered and cloned the CDK5 gene, which codes for a cyclin-dependent kinase enzyme. The majority of the other cyclin-dependent kinases are involved in cell division control, while CDK5 is not. Instead, it aids in the development of the central nervous system and aids in the regulation of synapse function.

CDK5 is activated by P35, a smaller protein with which it interacts. When P35 binds to CDK5, the structure of the enzyme alters, allowing it to phosphorylate (addition of a phosphate molecule to) its substrates.

CDK5 becomes highly active in cells when it binds to P25. CDK5 can also phosphorylate molecules other than its normal targets, such as the Tau protein, thanks to P25. Hyperphosphorylated Tau proteins generate the neurofibrillary tangles that are a hallmark of Alzheimer’s disease.
Tsai’s lab previously demonstrated that transgenic mice designed to express P25 experience severe dementia. P25 has been associated with various disorders in humans, including not only Alzheimer’s but also Parkinson’s and frontotemporal dementia.
Pharmaceutical companies have attempted to target P25 with small-molecule medicines, but because they also interact with other cyclin-dependent kinases, none of them have been evaluated in humans.

By employing a peptide instead of a tiny molecule, the MIT researchers opted to take a different approach to target P25. They created a peptide with a sequence that is comparable to a section of CDK5 known as the T loop, which is essential for CDK5 binding to P25. The complete peptide is just 12 amino acids long, which is slightly longer than the majority of currently available peptide medications, which are five to ten amino acids long.

“From a peptide drug point of view, usually smaller is better,” Tsai says. “Our peptide is almost within that ideal molecular size.”

The researchers discovered that treating neurons cultured in a lab dish with the peptide resulted in a moderate reduction in CDK5 activity. These studies also revealed that the peptide had no effect on the regular CDK5-P35 complex or other cyclin-dependent kinases.

When the peptide was evaluated in a mouse model of Alzheimer’s disease with hyperactive CDK5, the researchers observed a variety of favorable benefits, including reductions in DNA damage, brain inflammation, and neuron loss. These effects were far more significant in mouse investigations than in cell culture testing.

The peptide Alzheimer’s disease treatment also improved a distinct mouse model of Alzheimer’s disease, which had a mutant variant of the Tau protein that causes neurofibrillary tangles. Both Tau pathology and neuron loss were reduced in those mice after therapy. In addition to the impacts on the brain, the researchers found behavioral improvements. Mice treated with the peptide outperformed mice treated with a control peptide (a scrambled version of the peptide used to suppress CDK5-P25) in a task that requires learning to navigate a water maze, which relies on spatial memory.

The researchers injected the peptide into mice and discovered that it could cross the blood-brain barrier and reach neurons in the hippocampus and other areas.

The researchers also investigated the changes in gene expression that occur in mouse neurons following the new Alzheimer’s disease treatment -peptide therapy. Among the changes they discovered was an increase in the expression of roughly 20 genes that are normally triggered by the MEF2 family of gene regulators. Tsai’s lab previously demonstrated that MEF2 activation of these genes confers resilience to cognitive impairment in the brains of persons with Tau tangles, and she hypothesizes that the peptide treatment will have a similar impact.

Further development of such peptide inhibitors toward a lead therapeutic candidate, if proven to be selective for the target and relatively free of clinical side effects, may eventually lead to novel treatments for neurodegenerative disorders ranging from Alzheimer’s disease to Frontotemporal dementia to Parkinson’s disease,” says Stuart Lipton, a professor of neuroscience at Scripps Research, who was not involved in the study.

Tsai now plans to do further studies in other mouse models of diseases that involve P25-associated neurodegeneration, such as frontotemporal dementia, HIV-induced dementia, and diabetes-linked cognitive impairment.

“It’s very hard to say precisely which disease will most benefit, so I think a lot more work is needed,” she says.

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