Broader look at proteins involved in learning and memory

February 19, 2014 § Leave a comment

Schematic shows a protein array and parts of signaling pathways relevant to learning and memory. The yellow boxes indicate proteins that changed in level with normal learning. Image provided by Katheleen Gardiner.

Schematic shows a protein array and parts of signaling pathways relevant to learning and memory. The yellow boxes indicate proteins that changed in level with normal learning. Image provided by Katheleen Gardiner.

Learning is complicated business, but typical research studies into the molecular basis of learning and memory measure only one or a few proteins. In a study just reported in the journal Molecular & Cellular Proteomics, researchers cast a wider net and looked at 80 proteins in the brain of mice. By looking at more proteins, the study leader’s Katheleen Gardiner at the University of Colorado says researchers can get a better appreciation of “the greater complexity of molecular events underlying learning and memory, how components of a single pathway change in concert and how many pathways and processes respond.”

Gardiner’s research focus is on Down syndrome, two characteristics of which are that patients suffer from some level of intellectual disability and eventually develop Alzheimer’s disease. Gardiner’s group aims to find drugs that can lessen the learning disability. But, in order to do that, researchers need to better understand the molecular events associated with learning, memory, and neurodegeneration.

To get a grasp of the proteins involved in a particular learning process, the investigators studied context fear conditioning in mice. In this type of experiment, mice are put in a new cage and given a small electrical shock. Researchers can tell when a mouse has learned to be fearful of the same cage when the mouse freezes when put back in the cage. This approach “has the advantage that it requires only a single trial, lasting less than five minutes, for mice to learn,” explains Gardiner. “This means that we have a clear window in time where we know molecular events associated with successful learning occur.”

Context fear conditioning demands that the hippocampus, a region of the brain important for memory formation, be functional. The hippocampus is also a part of the brain that degenerates in Alzheimer’s disease.

The investigators gave the mice a drug called memantine, which is used to treat moderate to severe cases of Alzheimer’s disease. The drug has been shown to correct for learning impairment in a mouse model of Down syndrome.

Gardiner’s group used proteins arrays to see how protein expression changed in the brains of mice that underwent context fear conditioning and were given memantine compared with control mice. They found levels of 37 proteins changed in the nuclear fraction of hippocampus. Abnormalities in 13 proteins had been reported in brains of Alzheimer’s patients. “One surprise was that many proteins that increased in level with normal learning also increased, although not as much, with treatment with memantine alone,” says Gardiner. “Memantine induces responses in a substantial number of proteins that we measured, and it does this without impairing or enhancing learning. This indicates that there is considerable flexibility in the timing and extent of protein responses that still result in successful learning.”

In particular, Gardiner’s group identified the MAPK and MTOR pathways to be affected in their experiments, as well as subunits of glutamate receptors and the NOTCH pathway modulator called NUMB. NUMB is known to be essential for some aspects of brain development.

Gardiner says her group is now looking at data from a similar experiment done with a mouse model of Down syndrome. Those mice were unsuccessful with context fear conditioning, but they did as well as wild-type mice when they were treated with memantine.

Alzheimer’s disease fibrils keep their shape

September 12, 2013 § Leave a comment

Molecular structure of amyloid fibrils from patient 1. Image provided by Robert Tycko.

Molecular structure of amyloid fibrils from patient 1. Image provided by Robert Tycko.

One telltale sign of Alzheimer’s disease is the finding of clumps of a protein called beta-amyloid (Aβ) in the brain of a patient during autopsy. This protein forms fibrils with different structures, which go on to multiply and clump together. In a paper just out in Cell, researchers studied fibrils taken from two Alzheimer’s patients and discovered that the structure of a fibril persists as the fibril seeds the formation of more fibrils. The work has implications for the development for diagnostic and therapeutic approaches.

It’s possible to grow Aβ fibrils in test tubes by using synthetic Aβ peptides. But when that’s done, researchers get a mishmash of different fibril structures. When they realized this, Robert Tycko at the National Institute of Diabetes and Digestive and Kidney Diseases says he and his colleagues “began to wonder which structures actually form in brain tissue of Alzheimer’s disease patients.”

Tyko’s team in collaboration with that of Steven Meredith at the University of Chicago identified two patients who had different diagnoses for their dementia when they were alive. One patient was diagnosed initially with Lewy body dementia, but when she died and her brain was autopsied, pathologists found an abundance of Aβ clumps. The other patient was diagnosed with Alzheimer’s disease in the first place.

The investigators extracted Aβ fibrils from brain tissue samples of these two patients and used the fibrils as seeds to grow more fibrils in test tubes. They analyzed the fibrils by solid-state nuclear magnetic resonance and electron microscopy and showed that fibrils from each patient had highly uniform molecular structures.  There wasn’t a mishmash of different fibril structures. More importantly, the fibrils from the two patients were distinctly different from each other in molecular structure.

Tycko explains this finding may mean that “different Alzheimer’s disease patients can develop different fibril structures in their brains.  Results in this paper provide the first evidence that structural variations within Aβ fibrils may correlate with variations in clinical history.  This possibility needs to be examined carefully in future studies.”

The work also suggests that any diagnostic or therapeutic approaches need to be carefully tailored to the fibril structure. “Since specific fibril structures develop in Alzheimer’s disease brains, rather than a heterogeneous mixture of structures, it is important to develop amyloid-binding compounds for diagnostic imaging that target these specific structures,” says Tycko. “It may also be productive to design compounds that inhibit the formation of specific fibril structures, if certain structures, but not others, turn out to be more neurotoxic.”

Biomarker for Alzheimer’s disease in Down syndrome patient saliva?

April 2, 2013 § Leave a comment

Schematic to show biomarker identification in Down syndrome patients that link to Alzheimer's disease. Image provided by Tiziana Cabras.

Schematic to show biomarker identification in Down syndrome patients that link to Alzheimer’s disease. Image provided by Tiziana Cabras.

In a paper just out in Molecular & Cellular Proteomics, researchers report to have identified molecules in the saliva from people with Down syndrome that differ from those in healthy people. The tantalizing thing is that some of the identified molecules are thought to play roles in Alzheimer’s disease. As I briefly note in my latest cover story in ASBMB Today, Down syndrome patients can be particularly susceptible to Alzheimer’s disease.

Saliva contains biomarkers that act as early indicators for various conditions. The appealing thing about saliva is that it’s easy to collect — just spit into a tube and you’re done.

Because of saliva’s importance as a diagnostic fluid, a team led by Tiziana Cabras at the University of Cagliari in Italy wanted to see if it could find differences in biomarkers in those with Down syndrome. The investigators used a method called top-down proteomics to analyze all the salivary proteins in samples taken from 36 Down syndrome people. They then compared the salivary proteomes to those of sex- and age-matched control groups

Most intriguingly, Cabras and colleagues found that the levels of three proteins involved in immune responses, S100A7, S100A8 and S100A12, were increased significantly in the saliva of those with Down syndrome. The increase “may be of particular interest as biomarkers of the early onset Alzheimer’s disease, which is frequently associated with Down syndrome,” says Cabras. S100A7 has been previously shown to be a possible biomarker for Alzheimer’s disease.

Given this tantalizing, preliminary observation, Cabras says the researchers will recruit more patients to their study to see if the observation holds out. They also want to check to see if the same proteins also are increased in the saliva of Alzheimer’s disease patients and those with other neurological diseases. This would confirm that these proteins can act as salivary biomarkers to track the onset and progression of such diseases.

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