Hippocampal cells linked to fearful memories (green) were activated in Alzheimer's mice using optogenetics, which led to retrieval of lost memories.
Image credit: Dheeraj Roy
One of the earliest symptoms of Alzheimer's disease is memory loss, which gradually worsens as the disease progresses.
But senior author Susumu Tonegawa, of the Department of Brain and Cognitive Sciences at Massachusetts Institute of Technology (MIT), and colleagues suggest that individuals with early Alzheimer's still have the ability to form new memories - they just have difficulty retrieving them.
The researchers thought this might be the case following the results of a study they conducted last year, in which they found that mice with retrograde amnesia - memory loss caused by stress or trauma - had the ability to form new memories, despite having impaired memory recall.
In that study, Tonegawa and colleagues found they were able to retrieve the "lost" memories of these mice using a technique known as optogenetics, which involves the use of light to activate and control specific brain cells, or neurons.
This got the researchers thinking: could the same technique be used to retrieve memories that have been lost as a result of early Alzheimer's? This is what they set out to investigate with their latest research.
Retrieving lost memories using optogenetics
To reach their findings, the team genetically engineered two strains of mice so that they would develop clusters of beta-amyloid protein - known as plaques - in their brain, triggering memory loss; the same process is believed to cause memory loss in humans with Alzheimer's.
To test their memory loss, the researchers put the mice in a chamber alongside normal, healthy mice, where they all received an electric shock to the foot. When placed back in the chamber a few hours later, all mice showed fear.
- Around 5.3 million people in the US are living with Alzheimer's
- Of these, around two thirds are women
- Last year, Alzheimer's and other dementias cost the US around $226 billion.
When placed back in the chamber a few days later, however, the normal mice showed fear - suggesting they remembered the electric shock - while the Alzheimer's mice appeared to have no memory of 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," says lead study author Dheeraj Roy, also of the Department of Biology and Department of Brain and Cognitive Sciences at MIT.
Through using optogenetics, however, the researchers showed that these mice still had memories of the foot shock.
The team engineered the Alzheimer's mice to produce a light-sensitive protein called channelrhodopsin in neurons in the hippocampus - the brain region key for short-term memory - that are linked to fearful experiences.
The researchers placed the mice back into the chamber and activated the modified neurons by shining a light on them. They found that the mice showed fear immediately.
"Directly activating the cells that we believe are holding the memory gets them to retrieve it," says Roy. "This suggests that it is indeed an access problem to the information, not that they're unable to learn or store this memory."
However, when the Alzheimer's mice were put back into the chamber the following day, they showed no fear, suggesting that their memories of the foot shock had been lost once again.
Longer-term memory retrieval achieved
For the next part of the study, the researchers set out to see if they could use optogenetics to reactivate lost memories for longer.
For 3 hours, they repeatedly shone a light on cells within the entorhinal cortex of the Alzheimer's mice - cells that were connected to the cells in the hippocampus associated with the fearful memory. This brain connection is important for long-term memory storage.
A week later, the researchers placed the mice back into the chamber. They found that the mice showed fear once again, suggesting they remembered the foot shock, even in the absence of optogenetics.
What is more, the team found that the brain cells associated with the fearful memory had longer dendritic spines, which are protrusions from dendrites that enable neurons to communicate with others.
This increase in dendritic spine length suggests that the repeated optogenetic stimulation had boosted connections between the hippocampus and the entorhinal cortex; in Alzheimer's disease, these connections are usually broken down.
Commenting on the findings, Rudolph Tanzi, a professor of neurology at Harvard Medical School in Boston, MA, who was not involved in the research, says:
"This is a remarkable study providing the first proof that the earliest memory deficit in Alzheimer's involves retrieval of consolidated information. As a result, the implications for treatment of memory deficits Alzheimer's disease based on strengthening synapses are extremely exciting."
More precise memory-retrieval technique required for human use
The team notes, however, that optogenetic stimulation failed to work if the section of cells within the entorhinal cortex that was treated was too big, suggesting that the use of a memory-retrieval technique in humans would need to be very targeted.
The researchers say that while optogenetics is precise, it is too invasive for use in humans at present, and current methods available for human use - such as deep brain stimulation - target too much of the brain.
But Tonegawa says that there is hope for a more precise method for retrieving memories among patients with early Alzheimer's.
"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," he says. "Basic research as conducted in this study provides information on cell populations to be targeted, which is critical for future treatments and technologies."
Medical News Today recently reported on another study that found women may be able to hold on to their verbal memory skills for longer than men in the early stages of Alzheimer's.