AIDS Dementia Complex

Neuroscientists found a way to reverse neurodegeneration and other symptoms of Alzheimer's disease in mice by using a peptide to interfere with an enzyme that is typically overactive in the brains of Alzheimer's patients. MIT neuroscientists have found a way to reverse neurodegeneration and other symptoms of Alzheimer's disease by interfering with an enzyme that is typically overactive in the brains of Alzheimer's patients. When the researchers treated mice with a peptide that blocks the hyperactive version of an enzyme called CDK5, they found dramatic reductions in neurodegeneration and DNA damage in the brain. These mice also showed improvements in their ability to perform tasks such as learning 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 author of the study. "We saw wonderful effects in terms of reducing neurodegeneration and neuroinflammatory responses, and even rescuing behavior deficits." With further testing, the researchers hope that the peptide could eventually be used as a treatment for patients with Alzheimer's disease and other forms of dementia that have CDK5 overactivation. The peptide does not interfere with CDK1, an essential enzyme that is structurally similar to CDK5, and it is similar in size to other peptide drugs that are used in clinical applications. Picower Institute Research Scientist Ping-Chieh Pao is the lead author of the paper, which appears this week in the Proceedings of the National Academy of Sciences. Targeting CDK5 Tsai has been studying CDK5's role in Alzheimer's disease and other neurodegenerative diseases since early in her career. As a postdoc, she identified and cloned the CDK5 gene, which encodes a type of enzyme known as a cyclin-dependent kinase. Most of the other cyclin-dependent kinases are involved in controlling cell division, but CDK5 is not. Instead, it plays important roles in the development of the central nervous system, and also helps to regulate synaptic function. CDK5 is activated by a smaller protein that it interacts with, known as P35. When P35 binds to CDK5, the enzyme's structure changes, allowing it to phosphorylate -- add a phosphate molecule to -- its targets. However, 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. 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. 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. 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 take a different approach to targeting P25, by using a peptide instead of a small molecule. They designed their peptide with a sequence identical to that of a segment of CDK5 known as the T loop, which is a structure critical to the binding of CDK5 to P25. The entire peptide is only 12 amino acids long -- slightly longer than most existing peptide drugs, which are five to 10 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." Dramatic effects In tests in neurons grown in a lab dish, the researchers found that treatment with the peptide led to a moderate reduction in CDK5 activity. Those tests also showed that the peptide does not inhibit the normal CDK5-P35 complex, nor does it affect other cyclin-dependent kinases. When the researchers tested the peptide in a mouse model of Alzheimer's disease that has hyperactive CDK5, 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. Along with those effects in the brain, the researchers also observed behavioral improvements. Mice treated with the peptide performed much better in a task that required learning to navigate a water maze, which relies on spatial memory, than mice that were treated with a control peptide (a scrambled version of the peptide used to inhibit CDK5-P25). In those mouse studies, the researchers injected the peptide and found that it was able to cross the blood-brain barrier and reach neurons of the hippocampus and other parts of the brain. The researchers also analyzed the changes in gene expression that occur in mouse neurons following treatment with the peptide. Among the changes they observed was an increase in expression of about 20 genes that are typically activated by a family of gene regulators called MEF2. Tsai's lab has previously shown that MEF2 activation of these genes can confer resilience to cognitive impairment in the brains of people with Tau tangles, and she hypothesizes that the peptide treatment may have similar effects. 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. The research was funded by the National Institutes of Health.

KELOWNA, BC / ACCESSWIRE / August 31, 2022 / Lexaria Bioscience Corp. (Nasdaq:LEXX) (Nasdaq: LEXXW) (the "Company" or "Lexaria"), a global innovator in drug delivery platforms is pleased to announce its continued accumulation of international patent recognition with the receipt of its 27th worldwide patent granted in Mexico under registration #390001. This patent is from Lexaria's third patent family, "Stable Ready-to-Drink Beverage Compositions Comprising Lipophilic Active Agents" from which patents have already been issued in Australia, India and Japan. The patent is applicable to a range of active ingredients that includes but is not limited to non-psychoactive cannabinoids and NSAIDs. Types of products covered include certain pharmaceutical product formats as well as a wide variety of ready-to-drink consumer retail beverage products. Given Lexaria's continued pursuit of regulatory approval of DehydraTECH-CBD for the treatment of hypertension in regulated pharmaceutical applications, certain claims allowed in this new Mexican patent to use DehydraTECH-processed non-psychoactive cannabinoids to treat cardiac and cardiometabolic disorders are of particular value to the Company. Additional claims granted in Mexican patent #390001 include the treatment of neurological diseases such as Alzheimer's disease, Parkinson's disease, schizophrenia, and Human Immunodeficiency Virus (HIV) dementia; obesity; metabolic disorders such as insulin related deficiencies and lipid pro hepatic diseases, diabetes, and appetite disorders; cancer chemotherapy; benign prostatic hypertrophy; irritable bowel syndrome; biliary diseases; ovarian disorders; marijuana abuse; and alcohol, opioid, nicotine, or cocaine addiction. About Lexaria Bioscience Corp. Lexaria Bioscience Corp.'s patented drug delivery technology, DehydraTECH™, improves the way active pharmaceutical ingredients (APIs) enter the bloodstream by promoting more effective oral delivery. Since 2016, DehydraTECH has repeatedly demonstrated the ability to increase bio-absorption with cannabinoids, antiviral drugs, PDE5 inhibitors and more. DehydraTECH has also evidenced an ability to deliver some drugs more effectively across the blood brain barrier. Lexaria operates a licensed in-house research laboratory and holds a robust intellectual property portfolio with 27 patents granted and roughly 50 patents pending worldwide. For more information, please visit . CAUTION REGARDING FORWARD-LOOKING STATEMENTS This press release includes forward-looking statements. Statements as such term is defined under applicable securities laws. 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INVESTOR CONTACT: George Jurcic - Head of Investor Relations ir@lexariabioscience.com Phone: 250-765-6424, ext 202 SOURCE: Lexaria Bioscience Corp. View source version on accesswire.com: