Alzheimer's Disease  

Researchers 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.

R esearchers 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.

"Identifying small molecule compounds to restore LRP6 and the Wnt pathway, without inducing side effects, may help prevent or treat Alzheimer’s disease. This is a really exciting new strategy — a new and fresh approach."

“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.

Loss of LRP6 in neurons leads to enhanced buildup of amyloid protein, a pathological hallmark of Alzheimer's disease. Image Source - Mayo Clinic

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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.”


SOURCE  Mayo Clinic

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 Biological Regeneration  

Researchers discovered that green anole lizards turn on at least 326 genes in specific regions of a regenerating tail, including genes involved in embryonic development, response to hormonal signals and wound healing.

By understanding the secret of how lizards regenerate their tails, researchers may be able to develop ways to stimulate the regeneration of limbs in humans. Now, a team of researchers from Arizona State University is one step closer to solving that mystery. The scientists have discovered the genetic “recipe” for lizard tail regeneration, which may come down to using genetic ingredients in just the right mixture and amounts.

An interdisciplinary team of scientists used next-generation molecular and computer analysis tools to examine the genes turned on in tail regeneration. The team studied the regenerating tail of the green anole lizard (Anolis carolinensis), which when caught by a predator, can lose its tail and then grow it back.

The findings have been published recently in the journal PLOS ONE.

"By following the genetic recipe for regeneration that is found in lizards, and then harnessing those same genes in human cells, it may be possible to regrow new cartilage, muscle or even spinal cord in the future."

"Lizards basically share the same toolbox of genes as humans," said lead author Kenro Kusumi, professor in ASU's School of Life Sciences and associate dean in the College of Liberal Arts and Sciences. "Lizards are the most closely-related animals to humans that can regenerate entire appendages. We discovered that they turn on at least 326 genes in specific regions of the regenerating tail, including genes involved in embryonic development, response to hormonal signals and wound healing.”

Other animals, such as salamanders, frog tadpoles and fish, can also regenerate their tails, with growth mostly at the tip. During tail regeneration, they all turn on genes in what is called the ‘Wnt pathway’ — a process that is required to control stem cells in many organs such as the brain, hair follicles and blood vessels. However, lizards have a unique pattern of tissue growth that is distributed throughout the tail.

Overview of the stages of lizard tail regeneration. Source Kuzumi et al/PLOS ONE

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"Regeneration is not an instant process," said Elizabeth Hutchins, a graduate student in ASU's molecular and cellular biology program and co-author of the paper. "In fact, it takes lizards more than 60 days to regenerate a functional tail. Lizards form a complex regenerating structure with cells growing into tissues at a number of sites along the tail.”

"We have identified one type of cell that is important for tissue regeneration," said Jeanne Wilson-Rawls, co-author and associate professor with ASU’s School of Life Sciences. "Just like in mice and humans, lizards have satellite cells that can grow and develop into skeletal muscle and other tissues."

"Using next-generation technologies to sequence all the genes expressed during regeneration, we have unlocked the mystery of what genes are needed to regrow the lizard tail," said Kusumi. "By following the genetic recipe for regeneration that is found in lizards, and then harnessing those same genes in human cells, it may be possible to regrow new cartilage, muscle or even spinal cord in the future."

The researchers hope their findings will help lead to discoveries of new therapeutic approaches to spinal cord injuries, repairing birth defects, and treating diseases such as arthritis.


SOURCE  Science Daily

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