Novel storage mechanism allows command, control of memory

Introductions at a party seemingly go in one ear and out the other. However, if you meet someone two or three times during the party, you are more likely to remember his or her name. Your brain has taken a short-term memory - the introduction - and converted it into a long-term one. The molecular key to this activity is mTORC2 (mammalian target of rapamycin complex 2), according to researchers at Baylor College of Medicine in an article that appeared online in the journal Nature Neuroscience.

"Memory consolidation is a fundamental process," said Dr. Mauro Costa-Mattioli, assistant professor of neuroscience at BCM and corresponding author of the report. "Memories are at the center of our identity. They allow us to remember people, places and events for a long time, even a lifetime. Understanding the precise mechanism by which memories are stored in the brain will lead to the development of new treatments for conditions associated with memory loss".

Actin fibers

For the last five decades, neuroscientists have known that making long-lasting memories is dependent on the ability of brain cells (neurons) to synthesize new proteins. In their studies, Costa-Mattioli and his colleagues found a new mechanism by which memories are stored in the brain. The newly discovered mTORC2 regulates memory formation by modulating actin fibers, an important component of the architectural structure of the neuron.

"These actin fibers allow long-lasting changes in synaptic strength and ultimately long-term memories," said Wei Huang, a BCM graduate student and first author in the study.

Using genetically-engineered mice, the researchers found that turning off mTORC2 in the hippocampus (a crucial region required for memory formation) and surrounding areas allowed the animals to have a normal short-term memory, but prevented them from forming long-term memories. Similar to human patients with injury in the hippocampus, these mutant mice were no longer able to form new long-lasting memories.

According to Costa-Mattioli’s findings, mTORC2’s role is evolutionarily conserved and likely relevant to humans. Like mTORC2-deficient mice, fruit flies lacking TORC2 show defective long-term memory storage.

"Given that flies and mice last shared a common ancestor 500 million years ago, it is quite remarkable and telling that the function of mTORC2 in the regulation of memory is indeed maintained," said Dr. Gregg Roman, director of the Biology of Behavior Institute at the University of Houston, who contributed to the fly experiments.

Form long-term memories

The Holy Grail of memory neuroscience and to a certain extent, of industry efforts to produce a “smart drug,” has been the identification of molecules that promote the formation of long-term memory, said Costa-Mattioli. “We therefore wondered whether by turning on mTORC2 or even actin polymerization itself, we could form long-term memories more easily,” said Dr. Ping Jun Zhu, assistant professor of neuroscience at BCM, co-first author and senior scientist in Costa-Mattioli’s lab.

The team has identified a small molecule (a drug) that by activating mTORC2 and consequently actin polymerization enhances not only the synaptic strength between nerve cells but also long-term memory formation. In addition, the authors found that by directly promoting actin polymerization, with a second drug, long-term memory is generated more easily.

Costa-Mattioli’s team has identified two memory-enhancing drugs, but can they enhance memory in people? It is perhaps too early to say.

Huang said, “mTORC2, as far as we know, is really a new potential target for therapeutic treatments of human disorders. In the next few years, I predict we will see a lot of studies focusing on mTORC2 as a target.”

Memory cocktail

Costa-Mattioli’s short-term goals are to identify human cognitive disorders in which mTORC2 activity is dysfunctional and to see whether its restoration can return to normal impaired memory function in aging or even Alzheimer’s disease. But a small molecule alone might not do the job. Similar to the treatments for HIV or cancer, he believes that a combination of small molecules improving different aspects of memory formation will be required to efficiently treat cognitive disorders.

"We should start thinking about an efficient ‘memory cocktail’ rather than a single ‘memory pill.’ One molecule alone might not be enough. We may be years away from a decisive treatment, but I believe we are definitely on the right path," he said.

Others who took part in this work include Hongyi Zhou, Loredana Stoica and Mauricio Galiano, all of BCM, Krešimir Krnjević of McGill University in Montreal, Canada; and Shixing Zhang of the University of Houston.

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New model could lead to improved treatment for early stage Alzheimer’s

Researchers at the University of Florida and The Johns Hopkins University have developed a line of genetically altered mice that model the earliest stages of Alzheimer’s disease. This model may help scientists identify new therapies to provide relief to patients who are beginning to experience symptoms.

The researchers report their findings in the current issue of The Journal of Neuroscience.

“The development of this model could help scientists identify new ways to enhance brain function in patients in the early stages of the disease,” said David Borchelt, UF professor of neuroscience in the Evelyn F. and William L. McKnight Brain Institute and director of the SantaFe HealthCare Alzheimer’s Disease Research Center. “Such therapies could preserve brain function longer and delay the appearance of more severe symptoms that leave patients unable to care for themselves.”

In the early stages of Alzheimer’s disease, people struggle with and fail to learn new games, rules or technologies because their cognitive flexibility decreases. The degenerative disease continues with memory loss and the decline of other brain functions.

The researchers worked with mice that had specially designed gene fragments derived from bacteria and from humans that allowed the investigators to control the production of a small peptide. The peptide, called amyloid beta peptide, is a short chain of amino acids. Accumulations of this particular peptide in the brain as lesions called plaques occur early  in the progression of Alzheimer’s disease and seem to trigger the early memory problems.

The team regulated the expression of the peptide using antibiotics — when the animals stopped taking the antibiotic, the peptide-producing gene turned on and caused the mice to develop the plaques found in Alzheimer’s patients. After the mice had developed the Alzheimer pathology, the researchers turned the gene back off and observed that the mice showed persistent memory problems that resemble the early stages of the disease.

“This model may be useful to researchers to test drugs that could help with symptoms of early stage Alzheimer’s disease,” Borchelt said.This research is funded by the National Institute of Neurological Disease and Stroke of the National Institutes of Health, and the SantaFe HealthCare Alzheimer’s Disease Research Center of the University of Florida.

Researchers Identify Possible Treatment Window for Memory Problems

Researchers have identified a possible treatment window for plaques in the brain that are thought to cause memory loss in diseases such as Alzheimer’s, according to a new study published in the February 27, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Our study suggests that plaques in the brain that are linked to a decline in memory and thinking abilities, called beta amyloid, take about 15 years to build up and then plateau,” said Clifford R. Jack, Jr., MD, with the Mayo Clinic in Rochester, Minn.

For the study, 260 people between the ages of 70 and 92 underwent two or more brain scans over an average of 1.3 years that measured plaque buildup in the brain. Of the participants, 78 percent did not have impaired thinking abilities or memory at the start of the study.

The study found that the rate of buildup accelerates initially, then slows down before plateauing at high levels. For example, lower rates of plaque buildup were found in both people who had low and high levels of the plaques at the start of the study while the rate of plaque accumulation was highest in participants with mid-range levels at the start of the study.

The study also found that the rate of buildup of plaques was more closely tied to the total amount of amyloid plaques in the brain than other risk factors, such as the level of cognitive impairment, age and the presence of the APOE gene, a gene linked to Alzheimer’s disease.

“Our results suggest that there is a long treatment window where medications may be able to help slow buildup of the amyloid plaques that are linked to cognitive decline,” said Jack. “On the other hand, trying to treat the plaque buildup after the amyloid plaque load has plateaued may not do much good.”

Blood May Hold Clues to Risk of Memory Problems After Menopause

New Mayo Clinic research suggests that blood may hold clues to whether post-menopausal women may be at an increased risk for areas of brain damage that can lead to memory problems and possibly increased risk of stroke. The study shows that blood’s tendency to clot may contribute to areas of brain damage called white matter hyperintensities. The findings are published in the Feb. 13 online issue of Neurology, the medical journal of the American Academy of Neurology.

The study involved 95 women with an average age of 53 who recently went through menopause. The women had magnetic resonance imaging, or MRIs, taken of their brains at the start of the study. They then received a placebo, oral hormone therapy or the hormone skin patch. They had MRIs periodically over the next four years.

During the study, women with higher levels of thrombogenic microvesicles, the platelets more likely to cause blood to clot, were likelier to have higher increases in the amount of white matter hyperintensities (shown as concentrated white areas on an MRI scan), which may lead to memory loss.

"This study suggests that the tendency of the blood to clot may contribute to a cascade of events leading to the development of brain damage in women who have recently gone through menopause," says study author Kejal Kantarci, M.D., of Mayo Clinic. "Preventing the platelets from developing these microvesicles could be a way to stop the progression of white matter hyperintensities in the brain."

All of the women had white matter hyperintensities at the start of the study. The amount increased by an average volume of 63 cubic millimeters at 18 months, 122 cubic millimeters at three years and 155 cubic millimeters at four years.

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Alzheimer’s researchers trying brain zaps

It has the makings of a science fiction movie: zap someone’s brain with mild jolts of electricity to try to stave off the creeping memory loss of Alzheimer’s disease.

And it’s not easy. Holes are drilled into the patient’s skull so tiny wires can be implanted into just the right spot.

A dramatic shift is beginning in the frustrating struggle to find something to slow the damage of this epidemic: The first U.S. experiments with “brain pacemakers” for Alzheimer’s are getting under way. Scientists are looking beyond drugs to implants in the hunt for much-needed new treatments.

The research is in its infancy. Only a few dozen people with early-stage Alzheimer’s will be implanted in a handful of hospitals. No one knows if it might work, and if it does, how long the effects might last.

Kathy Sanford was among the first to sign up. The Ohio woman’s early-stage Alzheimer’s was gradually getting worse. She still lived independently, posting reminders to herself, but no longer could work. Medications weren’t helping.

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