The MIT neuroscientists report in Nature that mice in the early stages of Alzheimer’s can form new memories just as well as normal mice but cannot recall them a few days later. However, the researchers were able to artificially stimulate those memories using a technique known as optogenetics, suggesting that those memories can still be retrieved with a little help. Although optogenetics cannot currently be used in humans, the findings raise the possibility of developing future treatments that might reverse some of the memory loss seen in early-stage Alzheimer’s, the researchers say.
“As humans and mice tend to have a common principle in terms of memory, our findings suggest that Alzheimer’s disease patients, at least in their early stages, may also keep memories in their brains, which means there may be a possibility of a cure,” Susumu Tonegawa, the Picower Professor of Biology and Neuroscience and senior author of the study, told AFP.
“Even if a memory seems to be gone, it is still there. It’s a matter of how to retrieve it,” says Tonegawa.
In recent years, Tonegawa’s lab has identified cells in the brain’s hippocampus that store specific memories. The researchers have also shown that they can manipulate these memory traces, or engrams, to plant false memories, activate existing memories, or alter a memory’s emotional associations.
Last year, Tonegawa, who is director of the RIKEN-MIT Center for Neural Circuit Genetics, and Dheeraj Roy, an MIT graduate student who is the paper’s lead author, found that mice with retrograde amnesia, which follows traumatic injury or stress, had impaired memory recall but could still form new memories. That led the team to wonder whether this might also be true for the memory loss seen in the early stages of Alzheimer’s disease, which occurs before characteristic amyloid plaques appear in patients’ brains.
To investigate that possibility, the researchers studied two different strains of mice genetically engineered to develop Alzheimer’s symptoms, plus a group of healthy mice.
All of these mice, when exposed to a chamber where they received a foot shock, showed fear when placed in the same chamber an hour later. However, when placed in the chamber again several days later, only the normal mice still showed fear. The Alzheimer’s mice did not appear to remember the foot shock.
“Short-term memory seems to be normal, on the order of hours. But for long-term memory, these early Alzheimer’s mice seem to be impaired,” Roy says.
“An Access Problem”
“Directly activating the cells that we believe are holding the memory gets them to retrieve it,” Roy says. “This suggests that it is indeed an access problem to the information, not that they’re unable to learn or store this memory.”
“This is a remarkable study providing the first proof that the earliest memory deficit in Alzheimer’s involves retrieval of consolidated information,” says Rudolph Tanzi, a professor of neurology at Harvard Medical School, who was not involved in the research. “As a result, the implications for treatment of memory deficits Alzheimer’s disease based on strengthening synapses are extremely exciting.”
The researchers were also able to induce a longer-term reactivation of the “lost” memories by stimulating new connections between the entorhinal cortex and the hippocampus.
Optogenetics, which stimulates entorhinal cortex cells, is very precise but too invasive to use in humans, and existing methods for deep brain stimulation — a form of electrical stimulation sometimes used to treat Parkinson’s and other diseases — affect too much of the brain.
“It’s possible that in the future some technology will be developed to activate or inactivate cells deep inside the brain, like the hippocampus or entorhinal cortex, with more precision,” Tonegawa says. “Basic research as conducted in this study provides information on cell populations to be targeted, which is critical for future treatments and technologies.”