2. Neural Stem Cells ……………………………………………………………………. 3

3. Bone Marrow Stromal Cells …………………………………………………………. 3

4. Embryonic Stem Cells ……………………………………………………………….. 4

5. Limitations……………………………………………………………………………… 4

6. Conclusion …………………………………………………………………………….. 5

7. References……………………………………………………………………………...5Introduction Alzheimer’s disease (AD) is a degenerative disease in which nerve cells deteriorate and die, and synapses fail. Loss of cholinergic neurons has been implicated in AD. This causes cognitive impairment and memory loss. This disease affects approximately 5.3 million of Americans and is the sixth leading cause of death in the United States (Alzheimer’s Association 2009). As such, much research has been done to understand and treat this disease. A promising treatment lies in the use of stem cells. Stem cells, unlike normal cells, have the ability to remain unspecialized and give rise to specialized cells, a process called differentiation (NIH 2009). Thus, stem cells could differentiate into nerve cells and be used to replace the damaged or dead nerve cells in Alzheimer’s disease patients. This article will focus on recent research and the different strategies being studied to treat the disease. Figure 1 Summary Application of Stem Cells. Taken from Lindvall and Kokaia (2006) Neural Stem Cells Neural stem cells (NSC) have the ability to differentiate into three main groups of brain cells: neurons, astrocytes and oligodendrocytes. Current research done with neural stem cells deals with endogenous neural stem cells as well with exogenous stem cells. Xuan et al. (2009) managed to transplant neural stem cells using an Alzheimer’s disease model and testing the therapeutic effects of these cells. They also transplanted NSC derived glial cells. They evaluated the cognitive abilities of the mice by means of a maze test. The mice with NSC and glial cells graft presented an increase in cognitive ability over the control mice. They showed a marked improvement over the mice that only got the glial cell graft. These results show that neural replacement plays an important part in possible treatment for Alzheimer’s disease. These results also show that glial cells are also important because they provide neurothropic factors that protect the grafted and existing neurons from the damaging environment in which they are implanted. Another method makes use of the niche of neural stem cells present in adult brains. This requires the use of neurotrophins to promote neurogenesis, birth of new neurons. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell line derived neurotrophic factor (GDNF) could be used for this purpose. Neurogenesis occurs in selected areas of the brain. Research has shown that the brain retains two sites where new neurons are produced: the subventricular zone and the subgranule layer (Heese at al. 2007). An advantage of this method is that there is no risk of there being an immune response that rejects the cells, as could be the case with the grafts, since it uses the brains own neural progenitors. These methods focus on replacing the lost neurons, so that new synapses can form and thus improve cognitive ability. Bone Marrow Stromal Cells It was thought that stem cells from a particular area could only differentiate into cells closely related to its tissue of origin. However, experimental evidence suggests that cells derived from bone marrow could have application for neurodegenerative diseases. Wu et al. (2007) transplanted bone marrow cells into mice with an Alzheimer’s disease model. They showed that the transplanted cells differentiated into cholinergic neurons, which improved the cognitive ability of the AD mice. Also, they showed that the differentiated cells could not only survive, but also migrate into other affected areas different from the area of injection. One of the advantages of these cells is that they are easily attainable when compared to other types of stem cells. Embryonic Stem Cells Another method uses neural stem cells derived from embryonic stem cells (ESC). Spiliotopoulos et al. (2009) suggest that these neural stem cells differentiate more, so that greater numbers are produced. Also they declare that they are of better quality than stem cells acquired by other methods. However, transplanted ESC’s mostly differentiate into glial cells and a very low number into neurons. Limitations A more detailed pathology of Alzheimer’s disease is necessary to work out an effective treatment. AD affects many regions of the brain, involving the basal forebrain, amygdala, hippocampus and several cortical areas (Lindvall and Koksia 2006). Thus, the route of cell administration is a key issue. The multifocality of AD would require multiple transplants to repair the damage. Another issue that arises is if the new neurons will migrate to other damaged places or just remain in the site of transplantation. There is also the question if the grafted cells will survive in the damaging environment of an AD brain. Furthermore, will the new neuronal cells integrate into the nervous system or will they be rejected by the immune system? In addition, very large numbers of neurons would have to be replaced or repaired for a treatment to be successful (Heikkilä 2009). In the case of neural stem cells, protocols have to be developed to produce specific cell types. Experiments have shown that transplanted NSC’s have a tendency to differentiate mainly into glial cells and a small number into neurons. In the treatment of AD cholinergic neurons would have to be replaced, since they are greatly impaired and is thought that they play an important role in learning and memory. However, findings show that NSC’s have a tendency to differentiate mostly into dopaminergic neurons. For this reason, further research is needed to develop a protocol to differentiate NSC’s into the specific cell type needed (Imitola 2007). Conclusions There are still many unanswered questions in the use of stem cells for the treatment of Alzheimer’s disease. What would be the best source of stem cells? There have been experiments done with embryonic stem cells, neural stem cells and bone marrow stromal cells. Also, what would be the best approach? Should stem cells be transplanted or should we only use the brains’ own neural stem cells? Further research is needed for stem cells to be an effective therapy in the treatment of Alzheimer’s disease. However, recent studies evidence that research in this area should be pushed ahead and that it still remains a promising therapy. References Alzheimer’s Association. 2009 Alzheimer’s Disease Facts and Figures. 2009. Alzheimer’s & Dementia 5: 234–270 Heese K, Low JW, Inoue N. Nerve Growth Factor, Neural Stem Cells and Alzheimer’s Disease. 2006-2007 Neurosignals 15:1–12 Heikkilä TJ, Ylä-Outinen L, Tanskanen J, Lappalainen RS, Skottman H, Suuronen R, Mikkonen JE, Hyttinen JA, Narkilahti S. Human embryonic stem cell-derived neuronal cells form spontaneously active neuronal networks in vitro. 2009. Experimental Neurology 218: 109–116 Imitola J. Prospects for Neural Stem Cell-Based Therapies for Neurological Diseases. 2007. Neurotherapeutics 4: 701-714 Lee JK, Jin HK , Bae J. Bone marrow-derived mesenchymal stem cells reduce brain amyloid- deposition and accelerate the activation of microglia in an acutely induced Alzheimer’s disease mouse model. 2009. Neuroscience Letters 450: 136–141. Lerou PH, Daley GQ. Therapeutic potential of embryonic stem cells. 2005. Blood Reviews 19: 321–331. Lindvall O, Kokaia Z. Stem cells for the treatment of neurological disorders. 2006. Nature 441(29): 1094-1096 Pluchino S, Zanotti L, Deleidi M, Martino G. Neural stem cells and their use as therapeutic tool in neurological disorders. 2005. Brain Research Reviews 48: 211–219 Spiliotopoulos D, Goffredo D, Conti L, Di Febo F, Biella G, Toselli M, Cattaneo E. An optimized experimental strategy for efficient conversion of embryonic stem (ES)-derived mouse neural stem (NS) cells into a nearly homogeneous mature neuronal population. 2009. Neurobiology of Disease 34: 320–331. Stem Cell Basics [Internet]. [NIH] National Institutes of Health. [cited 2009]. Available from: http://stemcells.nih.gov/info/basics/ Sugaya K, Brannen C.L. Stem cell strategies for neuroreplacement therapy in Alzheimer's disease. 2001. Medical Hypotheses 57(6): 697-700 Wu QY, Li J, Feng ZT, Wang TH. Bone marrow stromal cells of transgenic mice can improve the cognitive ability of an Alzheimer’s disease rat model. 2007. Neuroscience Letters 417: 281–285 Xuan AG, Luo M, Ji WD, Long DH. Effects of Engrafted Neural Stem Cells in Alzheimer’s Disease Rats. 2009. Neuroscience Letters 450:167-171. Zeng X, Rao MS. Human embryonic stem cells: long term stability, absence of senescence and a potential cells source for neural replacement. 2007. Neuroscience 145:1348-1358.