MIT neuroscientists have found a way to reverse neurodegeneration and different Alzheimer’s illness signs by blocking an overactive enzyme, CDK5, in sufferers’ brains. Treating mice with a peptide inhibitor, they noticed important reductions in neurodegeneration, DNA injury, and improved cognitive skills. The peptide has the potential for use as a remedy for Alzheimer’s and different types of dementia with CDK5 overactivation, with out interfering with essential, structurally related enzymes.
The peptide blocks a hyperactive mind enzyme that contributes to the neurodegeneration seen in Alzheimer’s and different ailments.
MIT neuroscientists have discovered a strategy to reverse neurodegeneration and different signs of Alzheimer’s illness by interfering with an enzyme that’s sometimes overactive within the brains of Alzheimer’s sufferers.
When the researchers handled mice with a peptide that blocks the hyperactive model of an enzyme known as CDK5, they discovered dramatic reductions in neurodegeneration and DNA injury within the mind. These mice additionally confirmed enhancements of their means to carry out duties resembling studying to navigate a water maze.
“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 writer of the research. “We saw wonderful effects in terms of reducing neurodegeneration and neuroinflammatory responses, and even rescuing behavior deficits.”
With additional testing, the researchers hope that the peptide might finally be used as a remedy for sufferers with Alzheimer’s illness and different types of dementia which have CDK5 overactivation. The peptide doesn’t intrude with CDK1, an essential enzyme that’s structurally just like CDK5, and it’s related in measurement to different peptide medication which can be utilized in medical functions.
Picower Institute Research Scientist Ping-Chieh Pao is the lead writer of the paper, which was revealed on April 12 within the Proceedings of the National Academy of Sciences.
In the brains of mice handled with the brand new peptide (two proper panels), many fewer Tau proteins (stained purple) are seen within the prime proper. The left panels present neurons from mice handled with a scrambled model of the peptide. In the 2 backside panels, DNA within the cell nuclei is stained blue, displaying that the modifications in Tau ranges are usually not attributable to important modifications in cell inhabitants. Credit: Ping-Chieh Pao
Targeting CDK5
Tsai has been learning CDK5’s position in Alzheimer’s illness and different neurodegenerative ailments since early in her profession. As a postdoc, she recognized and cloned the CDK5 gene, which encodes a kind of enzyme often called a cyclin-dependent kinase. Most of the opposite cyclin-dependent kinases are concerned in controlling cell division, however CDK5 just isn’t. Instead, it performs essential roles within the improvement of the central nervous system, and in addition helps to control synaptic operate.
CDK5 is activated by a smaller protein that it interacts with, often called P35. When P35 binds to CDK5, the enzyme’s construction modifications, permitting it to phosphorylate — add a phosphate molecule to — its targets. However, in Alzheimer’s and different neurodegenerative ailments, P35 is cleaved right into a smaller protein known as P25, which might additionally bind to CDK5 however has an extended half-life than P35.
When certain to P25, CDK5 turns into extra energetic in cells. P25 additionally permits CDK5 to phosphorylate molecules apart from its standard targets, together with the Tau protein. Hyperphosphorylated Tau proteins type the neurofibrillary tangles which can be one of many attribute options of Alzheimer’s illness.
In earlier work, Tsai’s lab has proven that transgenic mice engineered to specific P25 develop extreme neurodegeneration. In people, P25 has been linked to a number of ailments, together with not solely Alzheimer’s but in addition Parkinson’s illness and frontotemporal dementia.
Pharmaceutical corporations have tried to focus on P25 with small-molecule medication, however these medication are inclined to trigger unwanted side effects as a result of additionally they intrude with different cyclin-dependent kinases, so none of them have been examined in sufferers.
The MIT staff determined to take a distinct strategy to concentrating on P25, by utilizing a peptide as a substitute of a small molecule. They designed their peptide with a sequence an identical to that of a phase of CDK5 often called the T loop, which is a construction crucial to the binding of CDK5 to P25. The total peptide is simply 12 amino acids lengthy — barely longer than most current peptide medication, that are 5 to 10 amino acids lengthy.
“From a peptide drug point of view, usually smaller is better,” Tsai says. “Our peptide is almost within that ideal molecular size.”
Dramatic results
In exams in neurons grown in a lab dish, the researchers discovered that remedy with the peptide led to a reasonable discount in CDK5 exercise. Those exams additionally confirmed that the peptide doesn’t inhibit the conventional CDK5-P35 advanced, nor does it have an effect on different cyclin-dependent kinases.
When the researchers examined the peptide in a mouse mannequin of Alzheimer’s illness that has hyperactive CDK5, they noticed a myriad of useful results, together with reductions in DNA injury, neural irritation, and neuron loss. These results had been far more pronounced within the mouse research than in exams in cultured cells.
The peptide remedy additionally produced dramatic enhancements in a distinct mouse mannequin of Alzheimer’s, which has a mutant type of the Tau protein that results in neurofibrillary tangles. After remedy, these mice confirmed reductions in each Tau pathologies and neuron loss. Along with these results within the mind, the researchers additionally noticed behavioral enhancements. Mice handled with the peptide carried out a lot better in a process that required studying to navigate a water maze, which depends on spatial reminiscence, than mice that had been handled with a management peptide (a scrambled model of the peptide used to inhibit CDK5-P25).
In these mouse research, the researchers injected the peptide and located that it was capable of cross the blood-brain barrier and attain neurons of the hippocampus and different components of the mind.
The researchers additionally analyzed the modifications in gene expression that happen in mouse neurons following remedy with the peptide. Among the modifications they noticed was a rise in expression of about 20 genes which can be sometimes activated by a household of gene regulators known as MEF2. Tsai’s lab has beforehand proven that MEF2 activation of those genes can confer resilience to cognitive impairment within the brains of individuals with Tau tangles, and she or he hypothesizes that the peptide remedy could have related results.
“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 concerned within the research.
Tsai now plans to do additional research in different mouse fashions of ailments that contain P25-associated neurodegeneration, resembling 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.
Reference: “A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes” by Ping-Chieh Pao, Jinsoo Seo, Audrey Lee, Oleg Kritskiy, Debasis Patnaik, Jay Penney, Ravikiran M. Raju, Ute Geigenmuller, M. Catarina Silva, Diane E. Lucente, James F. Gusella, Bradford C. Dickerson, Anjanet Loon, Margaret X. Yu, Michael Bula, Melody Yu, Stephen J. Haggarty and Li-Huei Tsai, 12 April 2023, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2217864120
The analysis was funded by the National Institutes of Health.
