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Adult Stem Cells Restore Memory in Mice

Proceedings of the National Academy of Sciences, July 21, 2009

Scientists at the Institute for Memory Impairments and Neurological Disorders at UC-Irvine have used neural stem cells derived from normal, healthy mice to treat other mice that had been genetically engineered to form the neurofibrillary plaques and tangles that characterize Alzheimer's disease. Just a month after receiving transplantation with the neural stem cells, the diseased mice were found to perform significantly better on memory tests. Further analysis revealed that the neural stem cells alone did not diminish the plaques and tangles in the brains of the mice, nor did the stem cells increase the number of neurons, but instead the stem cells were able to improve cognitive function by strengthening and increasing the number of connections between already existing neurons. The results of this study therefore offer very concrete evidence for the importance of "neural networks" - the brain's biological circuitry - in cognitive health. A hot topic in the 1990s, neural networks have proven to have a number of applications not only in neuroscience but also in computer engineering fields that include artificial intelligence. Among other things, the large-scale mathematical modelling of synaptic connections and their signaling resulted in the development of highly specialized "learning paradigms" and numerous types of neural network software which continue to have a broad range of applications to machine vision, mapping, virtual reality and any type of adaptive process. Now, a number of studies such as this, which are using stem cells to investigate the various mechanisms of the brain, are shedding further insights into a fundamental neurobiological process which translates readily to a wide variety of modern technological applications.

In the UC-Irvine study, the researchers found that most of the stem cells that were transplanted into the brains of the mice differentiated into astrocytes and oligodendrocytes, as only approximately 6% of the transplanted stem cells actually differentiated into neurons. Most importantly, the transplanted stem cells were found to secrete the protein BDNF (brain-derived neurotrophic factor) which stimulated the growth of neurites - a newly sprouted neuron that can grow into either an axon or a dendrite - thereby strengthening and increasing the number of connections between neurons. Conversely, when the scientists selectively reduced BDNF in the stem cells, the strength and number of the neuronal connections was observed to decrease, as did memory in the mice, thereby offering further evidence for the role of BDNF in maintaining healthy neuronal function and memory. When the scientists injected only the BDNF, without the stem cells, directly into the brains of diseased mice, some cognitive improvement was seen though not as much as when the BDNF was secreted directly by newly transplanted neural stem cells.

According to Dr. Mathew Blurton-Jones of UC-Irvine, the lead author of the study, "If you look at Alzheimer's, it's not the plaques and tangles that correlate best with dementia, it's the loss of synapses - the connections between neurons. The neural stem cells were helping the brain form new synapses and nursing the injured neurons back to health."

As Dr. Frank LaFerla, a coauthor of the study, adds, "Essentially, the cells were producing fertilizer for the brain. This gives us a lot of hope that stem cells or a product from them, such as BDNF, will be a useful treatment for Alzheimer's."

Alzheimer's disease is characterized by very specific neurological abnormalities which ultimately result in very specific types of behavioral abnormalities. Neurologically, there are 3 main identifying features of Alzheimer's disease, namely, 1) beta-amyloid plaques, which form outside and around neurons, 2) neurofibrillary tangles, which form inside dead neurons, and 3) overall dramatic shrinkage of neural tissue. The plaques and tangles in particular have come to be regarded as the hallmarks of Alzheimer's, although it is not yet known whether these features are a cause of the disease or merely a byproduct of the disease. The gross atrophy of the brain that is seen in advanced stages of Alzheimer's is a result of the widespread death of neuronal cells, and the concomitant loss of their synaptic connections. In severe cases the brain may be reduced by as much as a third of its normal size. Behaviorally, the symptoms of Alzheimer's disease are often mistaken in the early stages for a normal part of the aging process. However, Alzheimer's does not represent normal aging.

The website of the National Institute of Neurological Disorders and Stroke (NINDS), a branch of the National Institutes of Health (NIH), offers the following definition: "Alzheimer's disease is a progressive, neurodegenerative disease characterized in the brain by abnormal clumps (amyloid plaques) and tangled bundles of fibers (neurofibrillary tangles) composed of misplaced proteins." Also on the same website, the NINDS researchers further add that, "There is no cure for Alzheimer's disease and no way to slow the progression of the disease."

Indeed, prior to the advent of stem cell technology, conventional medicine offered no known effective therapy for Alzheimer's. Now, however, adult stem cell therapy may possibly offer the first type of treatment which not only slows the progression of the disease by eliminating the plaques and tangles, but which also reverses symptoms of the disease by regenerating new neurons.

Approximately 37 million people worldwide suffer from various forms of dementia, with Alzheimer's disease constituting the majority of cases. It has been estimated that 18 million people throughout the world are afflicted with Alzheimer's, approximately 5.3 million of whom are in the U.S., and these figures are expected to double by the year 2025. Although Alzheimer's is often associated with industrialized societies, currently over half of all people who suffer with this disease are reportedly living in developing nations.

In addition to U.S. President Ronald Reagan, many other prominent individuals have suffered from Alzheimer's disease, including the former Prime Minister of Britain, Harold Wilson, the choreographer George Balanchine, the composer Aaron Copeland, and the actress Rita Hayworth.

(Please see the related sub-section on this website, entitled "Alzheimer's Disease", listed in the "Research" section).



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