[Oct. 12, 2023: Staff Writer, The Brighter Side of News]
Previous attempts by pharmaceutical companies to target P25 with small-molecule drugs have been unsuccessful. (CREDIT: Creative Commons)
MIT scientists have discovered a potential treatment for Alzheimer’s disease by interfering with the activity of an enzyme that is typically overactive in the brains of Alzheimer’s patients.
CDK5, which is involved in the development of the central nervous system, becomes more active in cells when it binds to the protein P25. P25 also allows CDK5 to phosphorylate molecules, including the Tau protein which causes the formation of neurofibrillary tangles – a defining feature of Alzheimer’s disease.
Previous attempts by pharmaceutical companies to target P25 with small-molecule drugs have been unsuccessful. However, the MIT team has designed a peptide with a sequence identical to a segment of CDK5 known as the T loop, which is a critical structure in the binding of CDK5 to P25.
The peptide is slightly longer than most peptide drugs, which are usually five to 10 amino acids long. In tests with mice, the peptide caused dramatic reductions in neurodegeneration and DNA damage, along with behavioural improvements.
CDK5’s role in Alzheimer’s disease
Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and the senior author of the study, has been researching the role of CDK5 in Alzheimer’s disease and other neurodegenerative diseases since early in her career. CDK5 is a type of enzyme known as a cyclin-dependent kinase.
Unlike most other cyclin-dependent kinases, which are involved in controlling cell division, CDK5 plays an important role in the development of the central nervous system and regulates synaptic function.
CDK5 is activated by P35, a smaller protein that interacts with it. When P35 binds to CDK5, the enzyme’s structure changes, allowing it to phosphorylate its targets. In Alzheimer’s and other neurodegenerative diseases, P35 is cleaved into a smaller protein called P25, which can also bind to CDK5 but has a longer half-life than P35.
In the brains of mice treated with the new peptide (two right panels), many fewer Tau proteins (stained purple) are seen in the top right. The left panels show neurons from mice treated with a scrambled version of the peptide. In the two bottom panels, DNA in the cell nuclei is stained blue, showing that the changes in Tau levels are not caused by significant changes in cell population. (Credit: Ping-Chieh Pao)
When bound to P25, CDK5 becomes more active in cells. P25 also allows CDK5 to phosphorylate molecules other than its usual targets, including the Tau protein. Hyperphosphorylated Tau proteins form the neurofibrillary tangles that are one of the characteristic features of Alzheimer’s disease.
Previous attempts to target CDK5
In previous work, Tsai’s lab has shown that transgenic mice engineered to express P25 develop severe neurodegeneration. In humans, P25 has been linked to several diseases, including not only Alzheimer’s but also Parkinson’s disease and frontotemporal dementia.
A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes. (CREDIT: PNAS)
Pharmaceutical companies have tried to target P25 with small-molecule drugs, but these drugs tend to cause side effects because they also interfere with other cyclin-dependent kinases, so none of them have been tested in patients.
The MIT team decided to use a peptide instead of a small molecule to target P25. They designed their peptide with a sequence identical to that of a segment of CDK5 known as the T loop, which is a critical structure in the binding of CDK5 to P25. The entire peptide is only 12 amino acids long, slightly longer than most peptide drugs, which are usually five to 10 amino acids long.
The researchers tested the peptide in a mouse model of Alzheimer’s disease that has hyperactive CDK5, where they saw a myriad of beneficial effects, including reductions in DNA damage, neural inflammation, and neuron loss. These effects were much more pronounced in the mouse studies than in tests in cultured cells.
The peptide treatment also produced dramatic improvements in a different mouse model of Alzheimer’s, which has a mutant form of the Tau protein that leads to neurofibrillary tangles. After treatment, those mice showed reductions in both Tau pathologies and neuron loss.
Who has Alzheimer’s Disease?
In 2020, as many as 5.8 million Americans were living with Alzheimer’s disease.
Younger people may get Alzheimer’s disease, but it is less common.
The number of people living with the disease doubles every 5 years beyond age 65.
This number is projected to nearly triple to 14 million people by 2060.
Symptoms of the disease can first appear after age 60, and the risk increases with age.
What is known about Alzheimer’s Disease?
Scientists do not yet fully understand what causes Alzheimer’s disease. There likely is not a single cause but rather several factors that can affect each person differently.
Age is the best known risk factor for Alzheimer’s disease.
Family history—researchers believe that genetics may play a role in developing Alzheimer’s disease. However, genes do not equal destiny. A healthy lifestyle may help reduce your risk of developing Alzheimer’s disease. Two large, long term studies indicate that adequate physical activity, a nutritious diet, limited alcohol consumption, and not smoking may help people.
Changes in the brain can begin years before the first symptoms appear.
Researchers are studying whether education, diet, and environment play a role in developing Alzheimer’s disease.
There is growing scientific evidence that healthy behaviors, which have been shown to prevent cancer, diabetes, and heart disease, may also reduce risk for subjective cognitive decline.
What is the burden of Alzheimer’s disease in the United States?
Alzheimer’s disease is one of the top 10 leading causes of death in the United States.
The 6th leading cause of death among US adults.
The 5th leading cause of death among adults aged 65 years or older.
In 2020, an estimated 5.8 million Americans aged 65 years or older had Alzheimer’s disease. This number is projected to nearly triple to 14 million people by 2060.
In 2010, the costs of treating Alzheimer’s disease were projected to fall between $159 and $215 billion. By 2040, these costs are projected to jump to between $379 and more than $500 billion annually.
Death rates for Alzheimer’s disease are increasing, unlike heart disease and cancer death rates that are on the decline.
Dementia, including Alzheimer’s disease, has been shown to be under-reported in death certificates and therefore the proportion of older people who die from Alzheimer’s may be considerably higher.
For more science news stories check out our New Discoveries section at The Brighter Side of News.
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