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Cell death drug discovery: come at the king, you best not miss

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neurology

Seeing in triangles with grid cells

When processing what the eyes see, the brains of primates don’t use square grids, but instead use triangles, research from Yerkes neuroscientist Beth Buffalo’s lab suggests.

Elizabeth Buffalo, PhD

She and graduate student Nathan Killian recently published (in Nature) their description of grid cells, neurons in the entorhinal cortex that fire when the eyes focus on particular locations.

Their findings broaden our understanding of how visual information makes its way into memory. It also helps us grasp why deterioration of the entorhinal cortex, a region of the brain often affected early by Alzheimer’s disease, produces disorientation.

The Web site RedOrbit has an extended interview with Buffalo. An excerpt:

The amazing thing about grid cells is that the multiple place fields are in precise geometric relation to each other and form a tessellated array of equilateral triangles, a ‘grid’ that tiles the entire environment. A spatial autocorrelation of the grid field map produces a hexagonal structure, with 60º rotational symmetry. In 2008, grid cells were identified in mice, in bats in 2011, and now our work has shown that grid cells are also present in the primate brain.

Please read the whole thing!

Grid cells fire at different rates depending on where the eyes are focused. Mapping that activity across the visual field produces triangular patterns.

Posted on by Quinn Eastman in Neuro 1 Comment

Redirecting beta-amyloid production in Alzheimer’s

Pharmacologist Thomas Kukar is exploring a strategy to subtly redirect the enzyme that produces beta-amyloid, which makes up the plaques appearing in the brains of Alzheimer’s patients.

Thomas Kukar, PhD

Preventing beta-amyloid production could be an ideal way to head off Alzheimer’s, but the reason why a subtle approach is necessary was illustrated last year by disappointing results from a phase III clinical trial. The experimental drug semagacestat was designed to block the enzyme gamma-secretase, which “chomps” on the amyloid precursor protein (APP), usually producing an innocuous fragment but sometimes producing toxic beta-amyloid.

Gamma-secretase also is involved in processing a bunch of other vital proteins, such as Notch, central to an important developmental signaling pathway. Scientists suspect that this is one of the reasons why trial participants who received semagacestat did worse on cognitive/daily function measures than controls and saw an increase in skin cancer, leading watchdogs to halt the study.

While a postdoc at Mayo Clinic Jacksonville and working with Todd Golde and Edward Koo, Kukar identified compounds – gamma-secretase modulators or GSM’s — that may offer an alternative.

“We are looking at a strategy that’s different from global gamma-secretase inhibition,” he says. “The approach is: don’t inhibit the enzyme overall, but instead modify its activity so that it makes less toxic products.”

Gamma-secretase chomps on amyloid precursor protein, and how it does so determines whether toxic beta-amyloid is produced. It also processes several other proteins important for brain function.

This line of inquiry started when it was discovered that some anti-inflammatory drugs also could reduce beta-amyloid production. Then, the crosslinkable probes Kukar was using to identify which part of the gamma-secretase fish was doing the chomping ended up binding the bait (APP). This suggested that drugs might be able to change how the enzyme acts on one protein, APP, but not others.

Now an assistant professor at Emory, he is examining in greater detail how gamma-secretase modulators work. Two recent papers he co-authored in Journal of Biological Chemistry show 1) how the proteins that gamma-secretase chews up are “anchored” in the membrane and 2) how selective GSM’s can be on amyloid precursor protein.

Although clinical studies of a “first generation” GSM, tarenflurbil, were also stopped after negative results, Kukar says GSM’s still haven’t really been tested adequately, since researchers do not know if the drugs are really having an effect on beta-amyloid levels in the brain. Newer compounds coming through the pharmaceutical pipeline are more potent and more able to get into the brain. While looking for more potent GSM’s is critical, Kukar says it’s equally as important to understand how gamma-secretase works to understand its biology.

Posted on by Quinn Eastman in Neuro Leave a comment

Support from Family and Close Friends Helps Recovery

Representative Gabrielle Giffords

Representative Gabrielle Giffords. Photo courtesy Giffords’ House office.

As we watch the daily progress of Representative Gabrielle Giffords, many close observers have commented that her recovery has been moving along more quickly than expected, and took a big leap after the visit from President Obama.  Related?  Perhaps.

Emory Psychologist, Dr. Nadine Kaslow, says there is no question that love and support from family, friends, and others individuals a patient is close to, can make an enormous difference in the recovery process.

She explains that after people come out of a coma, they often seem to have a special connection to those who were there for them during the coma, even if they don’t actually remember anything in a conscious way. Efforts to communicate with the patient, she says, whether those be verbal or physical, can reinforce linking and communication. She adds patients who have physical contact from a loved one seem to visibly relax and engage more.

At Emory, as we move more and more to patient and family centered health care, we actively encourage loved ones to talk with the patient, read to the patient, touch and stroke the patient. Additionally, beds and shower facilities are provided so that family members can be with their loved ones around the clock.

Owen Samuels, MD, director of Emory University Hospital’s neuroscience critical care unit, reiterates that patient families are now recognized as central to the healing process and their presence can even reduce a patient’s length of stay. He says that in a neurology ICU, where the average length of stay is 13 days, but is often many, many more, this can be especially beneficial.

Posted on by Wendy Darling in Uncategorized Leave a comment
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