Targeting a Mechanism of Hyperphosphorylation in Alzheimer's Disease Pathology
Hyperphosphorylation of tau protein produces aggregation and neurofibrillary tangles in later stage Alzheimer's disease. Researchers here use a peptide to inhibit one of the mechanisms by which increased phosphorylation occurs in neurons in older individuals. The approach produces promising results in a mouse model of Alzheimer's disease, but - as is usually the case - one has to wonder as to whether or not this interaction of model and treatment in mice is relevant to the human condition. Old mice do not naturally develop any pathology resembling Alzheimer's disease, so all of the models are by their nature very artificial, and embody assumptions about which forms of pathology in the aging brain are most important. The outcome of this state of affairs is that many approaches to have worked well in mouse models went on to fail to achieve meaningful results in human patients, at great cost in time and funding.
Researchers have treated mice with a peptide that blocks the hyperactive version of an enzyme called CDK5, finding 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. The CDK5 gene 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.
Researchers have 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. This 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. 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.
Link: https://news.mit.edu/2023/new-peptide-may-hold-potential-alzheimers-treatment-0413