Posts tagged Wnt
Articles and news from the latest research reports.
Researchers Reveal Pathway that Contributes to Alzheimer’s Disease
Researchers at Jacksonville’s campus of Mayo Clinic have discovered a defect in a key cell-signaling pathway they say contributes to both overproduction of toxic protein in the brains of Alzheimer’s disease patients as well as loss of communication between neurons — both significant contributors to this type of dementia.
Their study, in the online issue of Neuron, offers the potential that targeting this specific defect with drugs “may rejuvenate or rescue this pathway,” says the study’s lead investigator, Guojun Bu, Ph.D., a neuroscientist at Mayo Clinic, Jacksonville, Fla.
“This defect is likely not the sole contributor to development of Alzheimer’s disease, but our findings suggest it is very important, and could be therapeutically targeted to possibly prevent Alzheimer’s or treat early disease,” he says.
The pathway, Wnt signaling, is known to play a critical role in cell survival, embryonic development and synaptic activity — the electrical and chemical signals necessary for learning and memory. Any imbalance in this pathway (too much or too little activity) leads to disease — the overgrowth of cells in cancer is one example of overactivation of this pathway.
While much research on Wnt has focused on diseases involved in overactive Wnt signaling, Dr. Bu’s team is one of the first to demonstrate the link between suppressed Wnt signaling and Alzheimer’s disease.
“Our finding makes sense, because researchers have long known that patients with cancer are at reduced risk of developing Alzheimer’s disease, and vice versa,” Dr. Bu says. “What wasn’t known is that Wnt signaling was involved in that dichotomy.”
Using a new mouse model, the investigators discovered the key defect that leads to suppressed Wnt signaling in Alzheimer’s. They found that the low-density lipoprotein receptor-related protein 6 (LRP6) is deficient, and that LRP6 regulates both production of amyloid beta, the protein that builds up in the brains of AD patients, and communication between neurons. That means lower than normal levels of LRP6 leads to a toxic buildup of amyloid and impairs the ability of neurons to talk to each other.
Mice without LRP6 had impaired Wnt signaling, cognitive impairment, neuroinflammation and excess amyloid.
The researchers validated their findings by examining postmortem brain tissue from Alzheimer’s patients — they found that LRP6 levels were deficient and Wnt signaling was severely compromised in the human brain they examined.
The good news is that specific inhibitors of this pathway are already being tested for cancer treatment. “Of course, we don’t want to inhibit Wnt in people with Alzheimer’s or at risk for the disease, but it may be possible to use the science invested in inhibiting Wnt to figure out how to boost activity in the pathway,” Dr. Bu says.
“Identifying small molecule compounds to restore LRP6 and the Wnt pathway, without inducing side effects, may help prevent or treat Alzheimer’s disease,” he says. “This is a really exciting new strategy — a new and fresh approach.”
Wnt Signaling Pathway Plays Key Role in Adult Nerve Cell Generation
Researchers from the University of Utah have gained new insight into the regulation of adult nerve cell generation in the hypothalamus, the part of the brain that regulates many aspects of behavior, mood, and metabolism. In the Sept. 10, 2012, issue of Developmental Cell they report that a cell-to-cell communication network known as the Wnt signaling pathway plays an important role in both the production and specialization of nerve cell precursors in the hypothalamus.
The hypothalamus is a highly complex region of the brain that controls hunger, thirst, fatigue, body temperature, and sleep. It also links the central nervous system to the body system that regulates hormone levels. Recent studies have shown that the hypothalamus is one of the parts of the brain in which neurogenesis, the birth of new nerve cells, continues throughout adulthood.
“In our earlier work, we discovered that Wnt signaling was required for neurogenesis in the embryonic zebrafish hypothalamus,” says Richard Dorsky, Ph.D., associate professor of neurobiology and anatomy at the University of Utah School of Medicine and senior author on the study. “We also found that, in zebrafish, both Wnt signaling and hypothalamic neurogenesis continue into adulthood. The goal of this study was to define specific roles for Wnt signaling in neurogenesis.”
The Wnt signaling pathway is a network of proteins that transmits signals from the cell surface to DNA in the cell nucleus to regulate gene expression, and it is known to play a critical role in cell-to-cell communication in both embryos and adults. In this study, Dorsky and his colleagues demonstrated that in zebrafish embryos Wnt signaling is present in progenitor cells that are actively multiplying in the hypothalamus. Progenitor cells have the potential to divide and differentiate into a variety of specialized cell types. Dorsky and his colleagues also found that Wnt signaling continues to be required for hypothalamic neurogenesis throughout life.
Neural progenitor cells arise from neural stem cells, and retain the capacity to develop into more specialized types of nerve cells. After the embryo is formed, some neural stem cells lie dormant in the brain and spinal cord until they are activated to serve as a repair system. When tissue damage or death occurs, chemical substances trigger these neural stem cells to make neural progenitor cells that assist in tissue recovery. Recent research suggests that other neural progenitor cells continue to make new nerve cells in the uninjured brain and contribute to the plasticity of the brain in response to changes in the environment.
“From a functional standpoint, it is not yet clear why the ability to continuously produce hypothalamic nerve cells is important in adult zebrafish,” says Dorsky. “However, in adult mice, hypothalamic neurogenesis seems to be significant in the regulation of feeding behaviors due to environmental changes.”
Dorsky and his colleagues discovered that the role of the Wnt signaling pathway differs between embryos and adults. In zebrafish embryos, activation of Wnt signaling is required for proliferation of progenitor cells contributing to growth of brain structures. However, at later stages of development including adulthood, Wnt signaling must be active for neural progenitor cells to commit to becoming nerve cells, but then must be inhibited for these cells to complete the differentiation process. Significantly, Dorsky and his colleagues also found that mice displayed a similar pattern of Wnt activity.
“Compared to other regions of the brain, the hypothalamus is relatively unstudied as a model of post-embryonic neurogenesis,” says Dorsky. “Our research represents a significant contribution to the field because it establishes the vertebrate hypothalamus as a model of Wnt-regulated neural progenitor differentiation that can be used to shed light on the plasticity of the adult brain.”
(Source: newswise.com)