Epilepsy Reduces The Formation of New Neurons in the Brain


An ambitious, multidisciplinary project led by Amanda Sierra and Juan Manuel Encinas, Ikerbasque from the Achucarro centre (Achucarro Basque Center for Neuroscience) has discovered that epilepsy in a mouse model system reduces the production of new cells in the brain.

The hippocampus is a region of the brain involved in learning and memory and it is also the site of a robust neural stem cell population that generates new neurons. These hippocampal neural stem cells generate new neurons throughout the adult life of mammals. The cells generated by the hippocampal neural stem cells function in certain types of learning and memory and in responses to anxiety and stress.

Hippocampus

This new research by Sierra and Encinas has revealed that in epileptic mice, hippocampal neural stem cells stop generating new neurons and are turn into reactive astrocytes. Reactive astrocytes promote inflammation and alter communication between neurons. Could manipulation of neural stem cells provide new ways to treat epilepsy?

Reactive Astrocyte
Reactive Astrocyte

This work has recently been published in the journal Cell Stem Cell.

The results of this research also confirms previous work by the same group that showed that epilepsy, which causes hyperexcitation of neurons but does not cause convulsions, activates neural stem cells, which leads to their premature exhaustion. Thus the generation of new neurons in the hippocampus ends is chronically reduced.

Juan Manuel Encinas, the leader of this study, highlighted the fact that “this discovery has enabled us to gain a better understanding about how neural stem cells function. We have shown that in addition to generating neurons and astrocytes, neural stem cells in the adult hippocampus can generate reactive astrocytes following an epileptic seizure.”

Encinas and his colleagues carried out this work in experimental animals that were genetically engineered to be epileptic. However, this discovery has clear implications in clinical practice and in the quest to develop new therapies for epilepsy, since the generation of new neurons (neurogenesis) is a process that is negatively affected in epileptic seizures in the hippocampus. Encinas pointed out, “If we can manage to preserve the population of neural stem cells and their capacity to generate new neurons in humans, it may be possible to prevent the development of certain symptoms associated with epilepsy and very likely to mitigate the damage that is caused in the hippocampus.”

In this project, Encinas and his colleagues collaborated with research groups attached to institutions such as the Baylor College of Medicine in Houston (United States), the Université Catholique de Louvain (Belgium), the Achucarro centre itself, and the UPV/EHU’s Genetic Expression Service.

Fat-Based Stem Cells Support New Brain Cell Growth in Alzheimer’s Disease Mice


Alzheimer’s disease (AD) causes progressive death of brain cells and dementia. The loss of memory, coordination, and eventually motor function is relentless and horrific, and causes extensive suffering, financial pressures and loss. Stem cell treatments have been proposed as a treatment for AD, but such treatments have met resistance because of the complex pathology of AD. Introducing new neurons into the brain will do little good if cells are normally dying. However, some work with laboratory animals has suggested that stem cell treatments can benefit animals with conditions that approximately AD (see Kim S, et al., PLoS One. 2012;7(9):e45757; Bae JS, et al., Curr Alzheimer Res. 2013 Jun;10(5):524-31). However there are few studies that examine the therapeutic effect of mesenchymal stem cells from fat tissue or “adipose-derived stem cells” on mice with AD, and the effect of these cells on the oxidative injury that tends to accompany AD, and if these stem cells stimulate the generation of new neurons in the brains of AD mice.

Now we have evidence that transplantation of mesenchymal stem cells can stimulate for formation of new brain cells in adult rat or mouse models of AD and improve tissue structure and function after a stroke. Dr. Yufang Yan and her team from the School of Life Sciences at Tsinghua University, China transplanted adipose-derived stromal cells (ADSCs) into a part of the brain known as the hippocampus of mice that express the APP/PS1 transgene. Such mice show an AD-like disease, with memory loss and amyloid plaques that form in the brain.

Transplantation of ADSCs in these AD model mice decreased oxidative stress and promoted the growth of new neurons and glial cells in the subgranular and subventricular zones of the hippocampus, and, consequently improved the cognitive impairment in APP/PS1 transgenic AD mice.

These findings were published in Neural Regeneration Research (Vol. 9, No. 8, 2014), and provide theoretical and experimental evidence that ADSCs can be used to treat AD patients.

Teaching Old Neural Stem Cells New Tricks


In our brains, cells called neurons produce nerve impulses and are responsible for thinking, learning memory, reasoning, and so on. Neurons do not exist in isolation, but in combination with cells called glial cells that support the neurons, nourish them, and protects them from stress damage. Neurons and glial cells are replenished by brain-specific neural stem cell populations in the brain.

Unfortunately, the neural stem cell population in our brains tends to produce far fewer neurons as they age. This deficit of new neurons can play a role in the onset of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Also, our own “senior moments” when we forget where we placed our iPod or car keys comes from a loss of neurons as we age.

Fortunately, some recent research might change this trend. A team from Japan’s Keio University, and the Riken national research institute, has reported the discovery of a small RNA molecule (micro-RNA) that controls neuron production in young mice. When this micro-RNA was manipulated in older mice, their neural stem cells started to make neurons again. The Japanese team also has reasons to believe that the same mechanism is at work in human brains as well. This research was reported in the journal Proceedings of the National Academies of Science. The mechanism is believed to exist in humans as well.

Senior Author Hideyuki Okano said, “We observed the neurogenic-to-gliogenic switching in developing NSCs.” Translation: Okano and his team examined embryonic mouse brains and their neural stem cell (NSC) populations. They found what many other groups have previously observed: that the developing embryonic brain NSCs create neurons first, then switch over to making glial cells later. Okano’s team also discovered the microRNA-17/106-p38 axis that is responsible for this initial neuron-to-glial cell switch during embryonic development.

When they manipulated this embryonic microRNA-17/106-p38 pathway in older, post-natal NSCs in culture, these older post-natal NSCs switched from making glial cells to producing neurons.

In culture, NSCs are difficult to control, since getting large supplies of neurons from cell cultures that various research groups call NSCs is very difficult.

Nevertheless, “there is general agreement that neurogenesis (make neurons) largely precedes gliogenesis (making glial cells) during CNS development in vertebrates,” Okano explained. And adult NSCs, according to Okano, clearly can produce neurons in the body, “whereas they exhibit strong gliogenic characteristics under culture conditions in vitro (that is, in the laboratory).”

Adult NSCs in two regions of the brain—the subventricular zone and hippocampus—also “make neurons, even though transplant studies have shown us that the adult CNS is a gliogenic environment.”

Subventricular Zone

So it seems clear that old NSCs can make neurons, at least under certain conditions. However, it is very difficult to determine the age at which NSCs begin making substantially more glial cells than neurons. According to Okano, “It is difficult to clearly explain the association between total glial cell number and changes in NSC abilities. Moreover, there is less evidence about gliogenic ability of aged NSCs because most of studies about NSCs have mainly focused on the neurogenic ability. “

Still, Okano says: “There are some reports about decline of neurogenesis ability of NSCs with age. These reports indicate that reduction in paracrine Wnt3 factors, and increase of (chemokine) CCL11 concentration in blood, impaired adult neurogenesis in the hippocampus, for example.”

Could the group’s microRNA approach improve memory in humans? Okano believes so, but says more work needs to be done.

“We observed the neurogenic effect by overexpression of miR-17 in primary cultured neurospheres” – spheres of a variety of cells, including NSCs—“derived from the SVZ at postnatal day 30. Similar phenomenon by overexpression of miR-106b-25 cluster has been reported by another group.”

Okano also warns that his approach has only been attempted in cultured cells. He cautioned, “There is no evidence using knock-out mice. Therefore, the functions of them in adult neurogenesis and learning/memory functions are still unclear.”

Next, Okano’s group will develop “a useful method for precise manipulation of cytogenesis from NSCs. “

However, he says, “we think that further understanding of basic molecular mechanisms underlying the neural development is also an important issue.” He will study the ways in which his microRNA system interacts with other glia-producing genes. He wants to fully understand the mechanisms underlying “the end of neurogenic competence and acquisition of gliogenic competence.”

Finally, the group will “examine the significance of miR-17/p38 pathway in various somatic stem cells other than NSCs,” he says.

Drug Corrects Brain Abnormalities in Mice With Down Syndrome


Down syndrome (DS) results when human babies have three copies of chromosome 21 rather than the normal two copies. However, three copies of pieces of chromosome 21 can also cause DS, and the region of chromosome 21 called the “Down Syndrome Critical Region” can also cause the symptoms of DS. The Down Syndrome Critical Region is located 21q21–21q22.3. Within this region are several genes, that, when present in three copies, seem to be responsible for the symptoms of DS. These genes are APP or amyloid beta4 precursor protein, SOD1 or Superoxide dismutase, DYRK or Tyrosine Phosphorylation-Regulated Kinase 1A, IFNAR or Interferon, Alpha, Beta, and Omega, Receptor, DSCR1 or the Down Syndrome Critical Region Gene 1 (some sort of signaling protein), COL6A1 or Collagen, type I, alpha 1, ETS2 or Avian Erythroblastosis Virus E26 Oncogene Homolog 2, and CRYAz or alpha crystalline (a protein that makes the lens of the eye).

All of these genes have been studied in laboratory animals, and the overproduction of each one of them can produce some of the symptoms of DS. For example, APP overproduction in mice leads to the death of neurons in the brain and inadequate transport of growth factors in the brain (see A.Salehi et al., Neuron, July 6, 2006; and S.G. Dorsey et al., Neuron, July 6, 2006). Also, the overexpression of CRYA1 seems to cause the increased propensity of DS patients to suffer from cataracts. Likewise, overexpression of ETS2 leads to the head and facial abnormalities in mice that are normally seen in human DS patients (Sumarsono SH, et al. (1996). Nature 379 (6565): 534–537).

People can also have only portions of the DS Critical Region triplicated and this leads to graded types of DS that only have some but not all of the symptoms of DS.

Why all this introduction to DS? It is among the most frequent genetic causes of intellectual disability. Therefore, finding a way to improve the cognitive abilities of DS patients is a major goal. T

There is a mouse strain called Ts65Dn mice that recapitulates some major brain structural and behavioral symptoms of DS and these include reduced size and cellularity of the cerebellum and learning deficits associated with the hippocampus.

Roger Reeves at Johns Hopkins University has used a drug that activates the hedgehog signaling pathway to reverse the brain deficits of Ts65Dn mice. Yes you read that right.

A single treatment given the newborn mice of the Sonic hedgehog pathway agonist SAG 1.1 (SAG) results in normal cerebellar morphology in adults.

cerebellum

But wait, there’s more. SAG treatment at birth also improved the hippocampal structure and function. The hippocampus is involved in learning and memory.

hippocampus

SAG treatment resulted in behavioral improvements and normalized performance in a test called the “Morris water maze task for learning and memory. The Morris water maze test essentially takes a mouse from a platform in shallow water and then moves the mouse through the maze and then leave it there. The mouse has to remember how they got there and retrace their steps to get back to the platform before they get too tired from all that swimming. Normally Ts65Dn mice do very poorly at this test. However, after treating newborn Ts65Dn mice with SAG, they improved their ability to find their way back.

SAG treatment also produced other effects in the brain. For example, the ratios of different types of receptors in the brain associated with memory are skewed in Ts65Dn mice, but after treatment with SAG, these ratios became far more normal. Also, the physiology of learning and memory was also more normal in the brains of SAG-treated Ts65Dn mice.

These results are extremely exciting. They confirm an important role for the hedgehog pathway in cerebellar development. Also, they suggest that the development of the cerebellum (a small lobe at the back of the brain involved in coordination and fine motor skills, direct influences the development of the hippocampus. These results also suggest that it might be possible to provide a viable therapeutic intervention to improve cognitive function for DS patients.

This excitement must be tempered. This is an animal model and not a perfect animal model. Also, it is unclear if such a compound will work in humans. Much more work must be done, but this is a fascinating start.

Neural Stem Cell Proliferation Increased By Herbal Extract


When it comes to herbal medicine, count me a skeptic. Some people swear by many herbs, but when these same herbs are objectively tested under controlled conditions, they fail spectacularly or they only show modest effects.

For example, a lady in my church is absolutely certain that Echinacea will cure your cold. However, a paper by Barrett in Phytomedicine, 2003 Jan;10(1):66-86 reviews several Echinacea trials and concludes that: “Although suggestive of modest benefit, these trials are limited both in size and in methodological quality. Hence, while there is a great deal of moderately good-quality scientific data regarding E. purpurea, effectiveness in treating illness or in enhancing human health has not yet been proven beyond a reasonable doubt.” Also the prestigious Cochrane database has examined many human trials that tested Echinacea and concluded that “Echinacea preparations tested in clinical trials differ greatly. There is some evidence that preparations based on the aerial parts of Echinacea purpurea might be effective for the early treatment of colds in adults but results are not fully consistent. Beneficial effects of other Echinacea preparations, and for preventative purposes might exist but have not been shown in independently replicated, rigorous randomized trials.” For this study, see Linde K, Barrett B, Wölkart K, Bauer R, Melchart D. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD000530,

When it comes to Ginkgo biloba extracts, the use of Ginkgo for age-related dementia has a veritable history, but the Cochrane reviews concluded: “The evidence that Ginkgo biloba has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unreliable.” See Birks J, Grimley Evans J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD003120. doi: 10.1002/14651858.CD003120.pub3.

Therefore, it is with some skepticism that I relate the following report to you.

Neural stem cells in the subventricular zone of the hippocampal dentate gyrus on adult mammals are responsible for learning and memory. These cells stop dividing during severe depression and dementia and expand during learning.

Hippocamus anatomy

The natural growth of these stem cells is insufficient to replenish cells after a severe stroke or in the event of serious brain disease. Therefore finding a way to stimulate these is important from a clinical standpoint.

Professor Yuliang Wang from Weifang Medical University has used an extract of Ginkgo biloba called EGb761 to treat rats with dementia. In their hands, this materials seems to safely treat memory loss and cognitive impairment (see Zhang Z, Peng D, Zhu H, Wang X. Experimental evidence of Ginkgo biloba extract EGB as a neuroprotective agent in ischemia stroke rats. Brain Res Bull. 2012 Feb 10;87(2-3):193-8).

Wang and his co-workers took this work one step further and examined the effects of EGb761 on the proliferation of neural stem cells in the subventricular zone and dentate gyrus of rats with vascular dementia.

According to Wang and others, the extract promoted and prolonged the proliferation of neural stem cells in the subventricular zone and dentate gyrus of rats with vascular dementia. The cells continued to proliferate for four months and improved learning and memory in rats with vascular dementia.

If you do not believe it, see Wang JW and others, Neural Regeneration Research 2013; 8 (18): 1655-1662.