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November 17, 2022
When a baby is born, each cell in its body contains 23 pairs of chromosomes, or 46 chromosomes in total, half of which come from each parent. At least, that’s the case for most of us.
The biological machinery responsible for ensuring proper distribution of chromosomes can sometimes go wrong. This can lead to a number of serious genetic diseases, the most common of which is known as Down syndrome. In this case, an extra copy of chromosome 21 is inherited from one parent. The condition is also known as trisomy 21.
In addition to a number of purely physical abnormalities, virtually all patients with Down syndrome develop Alzheimer’s disease, usually between the ages of 40 and 50. There are no treatments available to prevent or mitigate progression to Alzheimer’s disease for these people.
However, Arizona State University researcher Travis Dunckley and University of Arizona professor Christopher Hulme and their colleagues have developed a drug candidate that they hope can successfully block the development or progression of Alzheimer’s disease in patients with Down syndrome. The drug works by decreasing the levels of Dyrk1a, a particular type of enzyme known as a kinase, which is overexpressed in patients with Down syndrome.
“This particular kinase appears to be involved in many of the cognitive deficits in Down syndrome, and particularly in early-onset Alzheimer’s disease in Down syndrome,” says Dunckley, research assistant professor at the Research Center of Neurodegenerative Diseases ASU-Banner.
Dunckley and Hulme have founded a start-up company to push the new drug through further studies and develop it for human use. The company, Iluminos Therapeutics, LLC, has received a three-year, $3.5 million federal Small Business Technology Transfer Grant to test the latest iteration of the drug in a mouse model and conduct studies that allow the IND, thus positioning the compound for clinical trials.
If successful, the drug will be a medical milestone for people with Down syndrome. It may also represent a new approach to the treatment of late-onset Alzheimer’s disease, the most common form of dementia in the general population. Finally, the methodology can also be applied to other neurodegenerative diseases.
Illuminos team (left to right): Chris Hulme, Graduate Researcher James Foley, Travis Dunckley.
Many of the abnormalities associated with Down syndrome are thought to arise from a particular area of chromosome 21, known as the Down syndrome critical region. This portion of the chromosome contains a group of genes whose overexpression has been linked to telltale features of the disease, including craniofacial abnormalities and peripheral organ dysfunction, as well as the seeds of Alzheimer’s disease.
The design of the new drug was completed over a 10-year period by Hulme, an industry-trained medicinal chemist with experience developing drugs that inhibit the function of kinases. It will be directed by Ramon Velázquez, also an assistant professor at the Neurodegenerative Diseases Research Center tests in mouse models of the new kinase inhibitor drug.
Kinases are important regulatory enzymes in the body that add chemicals known as phosphates to other proteins. This phosphorylation process is fundamental to many life processes, playing a vital role in embryonic development. In Down syndrome, however, overphosphorylation of critical proteins can induce three classic hallmarks of Alzheimer’s disease.
When a protein known as amyloid beta precursor protein is hyperphosphorylated by Dyrk1a, the accumulation of amyloid beta plaques in the brain occurs. Hyperphosphorylation of another protein known as Tau causes neurofibrillary tangles within the cell bodies of affected neurons.
Dunckley and colleagues have also shown that hyperphosphorylation activity caused by Dyrk1a is linked to neuroinflammation, a common feature of neurodegenerative diseases, including Alzheimer’s disease. Research shows that overexpression of Dyrk1a is linked to elevated levels of an inflammatory cytokine known as TNF alpha.
The new drug is particularly exciting because it works to inhibit Dyrk1a, thereby targeting multiple neurodegeneration pathways. For this reason, it could break the deadlock of existing drug therapies, which typically target a single symptom, often after Alzheimer’s disease has already ravaged the brain beyond repair.
As Dunckley points out, the new insights into the relationship between Dyrk1a hyperactivity and the telltale symptoms of Alzheimer’s disease are the culmination of a long road of research and discovery.
“About 15 years ago, I wanted to try to identify new proteins responsible for Tau hyperphosphorylation, and through a series of high-throughput screens, we found that this Dyrk1a kinase was important in the process.”
In Down syndrome, hyperphosphorylation caused by Dyrk1a is an inevitable consequence of the chromosomal triplication produced by the disease, including the triplication of the Down syndrome critical region where the Dyrk1a kinase gene resides.
The research team will use a mouse model of Down syndrome to test a new version of the Dyrk1A kinase inhibitor they have spent years perfecting.
“Dyrk1a protein levels are elevated in human brain tissue from individuals with Down syndrome and in the mouse model of Down syndrome, suggesting that it may indeed play a role in the regulation of several pathogenic mechanisms. These include tau and amyloid beta pathology, as well as inflammation, which are seen in patients with Down syndrome and Alzheimer’s disease,” says Velázquez. “Having a drug that potentially improves these pathologies in Alzheimer’s disease but also in patients with Down syndrome is very motivating.”
The researchers will investigate the effects of various doses of the experimental drug on Alzheimer’s pathology in mouse models, as well as its ability to improve cognitive aspects associated with the disease, including spatial learning and memory.
Improvements in kinase inhibitor design have improved the drug in several ways. The latest version is very powerful and shows high selectivity, meaning it can narrowly distinguish Dyrk1a kinase from most of the other 500 kinases in the body. The inhibitor has a long half-life in the brain of about four hours and shows 100% bioavailability.
The first phase of the project will establish the efficacy of the kinase inhibitor in a mouse model relevant to Down syndrome. The next phase will establish that the drug is safe for human use. Since the first human recipients of the drug are likely to be teenagers with Down syndrome, the drug must meet a very high level of safety. Once achieved, however, this safety profile should later help secure FDA approval for wider use of the drug to treat Alzheimer’s in the general population.
Top image courtesy of iStock.com.
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Starbucks ’Pumpkin Spice Latte has been back for weeks and since mid-summer has been filled with seasonal stores, candles and many more stores across the country. Even if you’re not passionate about pumpkin spice fashion, there’s likely to be cinnamon and pepper in your life.
Why exactly are Americans addicted to pumpkin species?
According to perception researchers at Johns Hopkins University, it is the powerful smell. The smell of this autumn flavor often triggers familiar and welcoming memories: it creates a national nostalgia and increases the desire to reconnect with the coming season.
“The smells found in a pumpkin milk latte are found in many other things that are very strongly associated with this time of year, with positive memories such as family Thanksgiving or whispering autumn leaves and they go back to school, ”said Sarah Cormiea, Johns Hopkins, a doctoral student, studying human olfactory perception.
“Much of what you think is your sense of taste is actually your sense of smell,” he added. “When we eat, the olfactory particles can travel through the back of the nasal passages and activate the olfactory receptors … And the parts of the brain that process the smell are very close to the parts of the brain that process the information. the memory “.
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Getting rid of these fall memories can be seen in the increasing popularity of pumpkin species. Less than two decades after Starbuck launched its first PSL, demand for pumpkin species has skyrocketed. According to Nielsen and Forbes estimates, total sales of pumpkin products grew to more than $ 600 million in 2018, compared to $ 500 million in 2015.
A report from the Kearney Consumer Institute (KCI) further showed that pumpkin species are a much-loved flavor, noting that “scarcity creates demand,” which is part of the reason why species pumpkins are so popular that it is difficult to access them for two-thirds of the year. In a KCI survey, 60% of consumers noted that pumpkin species greatly influence the purchasing decision. Only 6% said the flavor is “overexposed or added to too many products.”
“In many facets of psychology, you observe this phenomenon called the familiarity effect or exposure effect,” said Jason Fischer, assistant professor in the Department of Psychological and Brain Sciences at Johns Hopkins. “The more you come across something and the more familiar you become, the more it takes root in your preferences … Pumpkin species come back every year, so now you feel like an old family friend, and even that in itself it can even generate preferences, towards that, because we usually like the things we are most familiar with. “
Everything is pretty impressive for the mix of aromas (albeit delicious) that don’t even include its eponymous ingredient, pumpkin. That is correct. The typical mixture consists of cinnamon, ginger, nutmeg and cloves or spices, but without pumpkin. Still, these spices together mimic the smell of cooked pumpkin and our minds fill in the gaps.
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The recognition of a well-known name, such as the now beloved “pumpkin species”, also works wonders. Cormiea stressed the power of labels and words related to smell in our consumer experience: making pumpkin species, for example, “even more spicy pumpkin”.
“Slapping the ‘Pumpkin Spice’ Label [a product] it reminds you of what it is … And, according to the research we do in our lab, we know that reading a label tends to make you remember the characteristics of the object you are smelling, including the things you remember about it. ” said Cormiea.
“You could probably make‘ spice latte ’taste like a‘ latte ’if you label it that way and put a picture of an apple next to it,” Fischer added.
Beyond labels, Fischer and Cormiea stressed the importance of recognizing our perceptions (including the power of our sense of smell) in everyday life, something that is too often overlooked, but that the fashion for pumpkin species is a perfect example.
“The more you pay attention to how you perceive the world at a given time, the more you will be able to act like your own scientist and delve deeper into your experience,” Fischer said.
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