Late Breaking News
Epidemic of Age-related Cognitive Disorders Looming
BETHESDA, MD—An increase in the quality and availability of health care and improvement in overall living conditions over the last century has helped increase average life expectancy in the United States from 55 years of age to over 75. It has also driven what some see as a looming epidemic of age-related cognitive disorders, especially Alzheimer’s disease. Some statistics show that 5% of the population over 65 is afflicted with varying levels of Alzheimer’s, and that the number doubles every 5 years thereafter, until one out of every two or three Americans over the age of 85 suffers the effects of the disease.
There are an estimated 5.3 million Americans suffering from AD, and 35 million suffering globally, with that number projected to increase to 65 million by 2030. Researchers around the world are searching for a way to turn the tide of this looming epidemic, with some asking the question, “Could stem cells be the answer?”
“Our memories are the core of our humanity,” explained Frank LaFerla, PhD, during a talk at the National Institutes of Health. Doctor LaFerla is an NIH-funded neuroscientist and director of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine. “Think of what your life would be like if you were no longer able to remember the basic aspects of your life. You know what kind of trouble you get into when your hard drive crashes. Imagine how you would feel if your brain starts to crash.”
“We have to ask ourselves whether this is going to be the reward for living a long life,” he pondered.
Doctor LaFerla and his colleagues developed the first mouse model of AD with both beta-amyloid plaques and tangles—the two defining lesions of AD—and provided the model free of charge to researchers around the world. Mouse models provide a good view of AD progression because mice breed quickly, age over a short lifespan, and their brain organization is comparable to that found in humans, Dr LaFerla explained.
Researchers once shied away from examining whether stem cells could treat AD primarily because of the profound amount of atrophy in a brain suffering from AD, which could lose as much as 40% of its mass due to cell loss. “I think it’s because there’s so much cell loss in the AD brain, most Alzheimer’s researchers, including me, did not think stem cells would be a viable treatment for Alzheimer’s disease. We were operating under the assumption that stem cells would only be effective if they replaced the dying cells that occurred.”
But as stem cell research progressed, and researchers searched for new avenues to treatAD, researchers began looking at how stem cells affected a brain with AD. “We were enthusiastic about using stem cells, because there’s no secret that there have been bumps in the road coming up with a treatment forAD,” Dr LaFerla opined.
Showing That Stem Cell Therapy Works
Doctor LaFerla and his fellow researchers started with their specially designed triple-transgenic mouse models that were 18 months of age and had extensive AD lesions. They injected neural cells into the neural tissue on both sides of the hippocampus, waited a month, evaluated them, and then sacrificed the subjects to examine them.
The evaluation included memory tests, which showed that the mice receiving the stem cells not only did better on the tests than those receiving no stem cells, but did as well as the mice not afflicted with the AD-similar lesions. “These were old animals with intensive plaques and tangles, with severe cognitive deficits, and yet we were able to rescue that with stem cells,” Dr LaFerla stated.
But how did the stem cells improve cognition? The researchers assumed that most of the stem cells would differentiate into neurons, since neurons were the types of neural cells most depleted by disease. However it was found that most were becoming astrocytes or oligodendrocytes, and only about 6% were becoming neurons.
“It was a very interesting result, but not what we expected,” Dr LaFerla said. “And we found that the stem cells were not really migrating toward the amyloid plaques.”
Doctor LaFerla and his team were stunned to find that the stem cells were having no effect on beta-amyloidpathology or tangle pathology. And yet the stem cells were having a distinct improvement on the animal phenotype.
Discovering Why Stem Cells Work
Frustrated over not understanding the mechanism of how the stem cells were improving cognitive function, Dr LaFerla and his fellow researchers looked away from the lesions and toward the best correlate of dementia—synaptic loss. As dementia progresses, there is a significant drop in the number of synapses in the affected brain.
They found that the animals that had received the stem cells had far more synapses compared to those that did not receive the dose…almost a doubling of synaptic markers. The stem cells were leading to the creation of more brain-derived neurotrophic factor expression in the animals’ brains. BDNF is a protein that helps existing neurons survive and encourages the growth of new neurons.
Further studies confirmed that it was an increase of BDNF having the cognitive improvement. When the researchers injected BDNF into mice they found a significant increase in synaptic density in the subjects treated just once with BDNF. This opens up the possibility that BDNF can be used instead of stem cells…an easier method of treatment should the technique be translated into a human clinical trial, Dr LaFerla noted.
Next, the researchers tested to see if stem cells would have any effect on cell loss in the brain. Doctor LaFerla and his team created a mouse model with brain loss and then induced a lesion in the CA1 area of the brain located in the hippocampus. They implanted stem cells and then tested the animals for synaptic improvement.
“In the lesioned animal, the stem cells tended to all stay in the hippocampus. In the non-lesioned animal, they tended to migrate out into the cortex,” Dr LaFerla explained. “There seems to be something about the damaged hippocampus that keeps the stem cells in that area.”
When examined at the three-month point, the mice showed a marked improvement with cells increasing BDNF expression which lead to increased synaptic density.
The Future of Therapy
There is still a lot of work to do before some kind of stem cell-based therapy will be available for humans. That work includes grafting human cells into mice. “What we’ve done so far is to put mouse cells into the mouse brain. But to advance this to the clinic, we need to put human cells into the mouse brain,” Dr LaFerla explained.
There is also the problem of what stem cells to use should the therapy ever progress to the point of being used on humans. One question that researchers frequently ask, Dr LaFerla noted, is whether scientists can personalize this therapy and take induced pluripotent cells from a patient to use for that patient’s therapy.
“That will be unlikely,” he said. “When you’re talking about 5.3 million people afflicted with AD, it’s unlikely that you’ll be able to grow 5.3 million cells under good manufacturing conditions for this process to become a viable therapy.”
For this promising therapy to become practical, researchers will need to come up with a generic human cell line that can be used on as wide a variety of people as possible, Dr LaFerla said. Still, he sees this being tested on humans in the relatively near future. “Hopefully we will be situated in 3 to 4 years to undertake a human clinical trial looking at this for AD,” he said.