What was Old is New Again: Scientists Transplant Brain Cells into Aged Mice and Reverse Memory Loss

Alzheimer’s disease starts with small, almost imperceptible steps. And then it builds. Sometimes slowly over a period of decades, other times more quickly—in just a matter of years. But no matter the speed of progression, the end outcome is always the same.

Transplanted cells (shown in green) in the hippocampus, 3 months after transplantation.  Cell nuclei are labeled in blue.  [Credit: Leslie Tong and Yadong Huang/Gladstone Institutes]

Transplanted cells (shown in green) in the hippocampus, 3 months after transplantation. Cell nuclei are labeled in blue. [Credit: Leslie Tong and Yadong Huang/Gladstone Institutes]

The sixth leading cause of death in the United State, Alzheimer’s develops as brain cells, or neurons, are destroyed over time. The hippocampus, the brain’s memory center, is the hardest hit, which is why memory loss is the single most common—and most devastating—symptom of the disease.

As a result, scientists have looked to the field of regenerative medicine to replace the vital cells lost to Alzheimer’s. And now, researchers at the Gladstone Institutes in San Francisco have made an important step towards that goal.

Reporting in the latest issue of the Journal of Neuroscience, researchers in the laboratory of Dr. Yadong Huang have successful transplanted early-stage brain cells, called “neuron progenitor cells,” into aged mice that have been modified to mimic Alzheimer’s symptoms. And after doing so, what they saw was extraordinary.

Not only did the cells survive the transplantation—a feat in and of itself—they began to grow and integrate into the molecular circuitry of the brain. And that’s when they noticed changes to the animals’ behavior.

These mice, whose age corresponded to humans in late-stage adulthood, were living with physical signs of memory loss. But after the cell transplants, the team saw signs that memory and learning were restored.

Leslie Tong, a graduate student at Gladstone and the University of California, San Francisco and the paper’s first author, elaborated on the importance of these findings in a news release:

“Working with older animals can be challenging from a technical standpoint, and it was amazing that the cells not only survived but affected activity and behavior.”

For a brain to function normally, there should be a balance between two types of neurons: ‘excitatory’ neurons, that act as the brain’s gas pedal, and ‘inhibitory’ neurons that serve as the brake. If this balance between these two cell types gets thrown out of whack, normal function is disrupted—and cells, especially the inhibitory neurons, degrade and die. Combined with other factors, such as genetic risk and the buildup of toxic proteins—this imbalance plays a key role in the dysfunction that eventually leads to Alzheimer’s.

The success of this treatment not only reveals the importance of maintaining this balance in memory and learning, but is also proof of concept that if neurons are lost—they can in principle be replaced.

Huang is particularly excited about the therapeutic potential of these findings. As he stated in the same news release:

“The fact that we see a functional integration of these cells into the hippocampal circuitry and a…rescue of learning and memory deficits in an aged model of Alzheimer’s disease is very exciting.”

This study, which was supported in part by CIRM, points towards several possible therapeutic strategies that could one day help human brains ravaged by Alzheimer’s regrow the cells they’ve lost—and repair the damage to learning and memory that today remains irreparable. According to Huang:

“This study tells us that if there is any way we can enhance inhibitory neuron function in the hippocampus, like through the development of small molecule compounds, it may be beneficial for Alzheimer’s disease patients.”

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