Stem cells and Alzheimer's disease

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A stem cell is one of the master cells in the human body that has potential ability of growing into any of the more than the body's 200 cell types. All of them are unspecialized and they are characteristically from the same lineage. They have the ability to divide themselves for the rest of their lifetime giving rise to new cells which in return emerge to be very specialized taking places left by dead cells. They play a very significant role in renewing body tissues. They have a unique characteristic due to their ability to both create new cells irrespective of which tissue they are in and to renew themselves. This is in contrast to mature cells that have a permanent commitment to their fate. From research studies, it is believed that stem cells have the ability to cure Alzheimer's disease.

Alzheimer's disease affects the brain and it's named after a German scientist Alois Alzheimer who first described it in 1907. Today, this brain disorder is characterized as progressive and fatal, causing degeneration and dysfunction of synapses and neurons in the brain region critical for learning and memory function. It's identical to more common senile dementia beginning after 65 years. In United States of America for example, research indicates that almost 5.3 million Americans are victims of Alzheimer's. It is a disease that highly causes damage to brain cells resultant effects being memory loss. Other characteristics include amyloid plaques and neurofibrillary tangles causing neuronal degeneration. Major problems of severe effect are seen in the victim's behavior and thinking. It's a progressive neurodegenerative disease leading to severe incapacity and death. This eventually affects a person's lifelong hobbies, work and social life. It is because of continuous research on the stem cells and their believed ability to cure this fatal disease that has created documented facts that Alzheimer's gets worse over time. In the United States, it is the seventh among the disease that causes most deaths. Of all forms of dementia (memory loss), Alzheimer's is the most common. It accounts for 50 to 70% of all cases of dementia. Diagnosis of Alzheimer's requires looking at the patient's history first. What follows after this is use of psychological testing, brain imaging or an autopsy is performed where this disease is confined. It has been indicated that there are no specific changes in routine laboratory examination. Research has shown that brain imaging has that potential to become important in diagnosis of Alzheimer's. Magnetic Resonance Imaging (MRI), a medical imaging technique in radiology has also been used to visualize internal structure of the brain tissue when its functioning is limited. MRI helps to reveal dilatation of the cortical cells particularly in temporal regions.

Putative stem cells are the cells with the ability to divide and self-replenish producing daughter cells capable of transitioning themselves into differentiated types of cells. These putative stem cells have for long been understood to exist in most adult human tissues like muscle, intestine and bone marrow. Cells from bone marrow are used to replace immune and hematopoietic systems in disease therapies. Today, it is held that human adult brain harbor stem cells capable of generating all types of neural cells. Recent research in mouse stem cells indicate that when adult stem cells are manipulated and taken into appropriate environments, they capable of forming cells types which are same as their origin. Samples were taken from bone marrow that showed they do integrate into skeletal myofibers, neuron-like cells and glial cells in central nervous system forming oval cells in the liver.

As the mouse ages, there are some hematopietic stem cells that create cardiomyocytes replacing cells that have been damaged in the heart. In the same manner, stem cells from the muscles do replenish hematopietic compartment while stem cells from the nervous system form skeletal muscle cells and blood elements. Research from mouse stem cells and their differentiation has also shown that they can differentiate even more than it was first thought. It thus shows adult stem cells have similar possibilities in tissue replacement therapy. Thus, following what has been understood from the studies of mouse stem cells, it is possible to understand how human adult stem cells differentiate and divide. Through this understanding, it becomes possible for bone marrow stem cells to be grafted so that they can replace lost cells through injury and disease as people age. So many body tissues undergo changes that become detrimental to quality of life and health in aging people (, 1998). Muscles have a good supply of stem cells so that they can maintain and replace muscle mass and muscle fibers. However, despite the good supply of stem cells they still experience changes in types of fibers, muscle mass loss and many other changes that weaken them as people become elderly. Bones become brittle and weak because of the changes in remodeling and turnover. These changes are due to alteration in balance between different cell types from bone marrow precursors. There are several parts of the brain in humans that are left with the ability to generate new glia and neurons. However, brain and neuronal dysfunction still occur with aging. Some researches have shown that this happens partly because of the supply of stem cells that continue to diminish as one ages. Resident stem cells become susceptible to damage mechanisms which cause senescence at tissue and cell levels. Fundamental to aging of organisms is the changing supply volumes and stem cells potential to replace cells in the tissue turnover.

There are several types of stem cells which include; embryonic, fetal, adult, endogenous and synthesized stem cells. All these stem cells are characterized by their capacity to self replicate, i.e. they self renew themselves. They are said to be teratogenic (able to disturb developing embryo/fetus). Stem cells have pluripotency (capacity to have more than one outcome) and they contribute to homeostasis and repair. Stem cells meant to differentiate to definite cell types present the prospect of a renewable source of substitute cells and tissue to cure diseases like Alzheimer's, Parkinson's disease, stroke, heart disease, burns, Rhumatic arthritis, spinal cord injury, diabetes mellitus and Osteo arthritis. A victim of Alzheimer's disease has abnormal elevation of Fibroblast Growth factor 2 (FGF2) associated with dysregulation of dentate gyrus neurogenesis (Tabebayashi et al, n.d). Pathology in neurogenesis is purely a therapeutic target. Main stem cells used in Alzheimer's disease are Human Embryonic stem cells (hESC) and adult stem cells. The adult stem cells that are mainly used in Alzheimer's disease may include testicular, olfactory, mammary, hermatopoietic, mesenchymal, adipose derived adult stem cells and neural stem cells. Studies have shown that neuronal stem cells are important in treating neurologic diseases such as spinal chord injuries, Huntigoten disease, Multiple Sclerosis, Parkinson disease, Amyotropic lateral sclerosis (ALS), Alzheimer's disease and stroke. It is possible for neuronal stem cells to differentiate into each of the diverse brain cell types like Astrocytes, oligodendrocytes and neurons. There is involvement of amyloid-B precursor protein and the presenilins in Neural Stem Cells (NSCs) biology and possible application of NSCs for therapeutic approaches in Alzheimer's disease (Sugaya & Brannen, n.d).

According to Baker (2002), a few hours and days after a person experiences stroke, stem cells usually leave the bone marrow. They do this in order to assist the injured brain to start repairing the damaged neurons, make new blood vessels and new neurons. At the Medical College of Georgia, a research on stroke was conducted using a mouse. The marrow of the mouse was replaced with marrow from a transgenic mouse that had cells making a jelly fish protein. This jellyfish protein fluoresces green to enable the researchers trace cells together with the natural process of tissue repair occurring immediately after experiencing stroke. In the mouse model, these researchers found that bone marrow cells migrate naturally to injured parts of the animal's brain immediately after stroke so that they can help in repairing of damaged tissues. These stem cells that migrate become endothelial cells which eventually form new vessels of blood appearing as neurons. It is the bone marrow that has stem cells that is primarily involved in such repairs and this normally occurs naturally when responding to stroke. Embryological development comes after these repairs yet it is indicated that elderly individuals have fewer circulating stem cells compared to the younger generation that is healthier.

A brain repair program was arranged by NeuroScience Canada in 2003to generate innovative and excellent brain repair (Neuroscience, 2009). Out of the teams that were competing, their findings indicated that stem cells are new cells that have a harbor for repair of injured nervous system and brain. In their findings, they indicated that those stem cells from the skin dermis (skin layer under the epidermis layer) generate nervous system cells. These generated cells placed in a mouse that has experienced a spinal cord injury have ability to regain the movement and function of a limb. For example in Parkinson's disease, animal and brain cells that are fetal are implanted in the brains of human. These are cells that produce chemicals required by the brain so that it can control movement (L-Dopa). In this case, such an implant provides the missing chemical messenger. Recent past saw scientists looking for findings on brain damage repair. Most of their findings show that there are plenty of uncommitted neural cells that are embryonic (neural stem cells). These were found to be located in the specialized areas of the nervous system where the sense of smell is. This is taken to be a very vital skill in animals as it's used in getting food, sexual behavior and environment recognition. It was established by their studies that when smell neurons are destroyed or lost, it is the neural stem cells that replace them.

In adult humans, a bank of sensory stem cells was discovered in the sensory nervous system. Trauma and infections destroy most of these sensory cells which are mostly replaced by stem cells as it is done in animals. When these stem cells mature, they copy the local characteristics that are controlled by the environment. All cells have complete genetic code. Thus anything local eventually activates the genes and this in turn makes a maturing stem cell to copy characteristics of the local environment. Most of the scientists have revealed through research that human stem cells could only be seen in the bone marrow and embryos where they are committed in production of blood cells. However, today's research has been credited with establishing that stem cells are also well found in adults specifically in the eye and brain. These stem cells replace dead neurons which are located in the olfactory bulb. This is the human organ that is specialized in transfer of scent signals to hippocampal dentate gyrus (organ that organizes short-term memory) and the brain. In a developing embryo, it is the work of the stem cells to give rise to different types of cells. These are the cells that make up the brain, muscle, blood, skin, nerves and other parts of the body. Some of them remain in adults and they give rise to stomach lining and skin cells. Some other researchers have said that it is not all stem cells that can be used or applied in replacement theory. They assert that a stem cell producing neurons which are vital in neural replacement in cerebral cortex (neurons lost in Alzheimer's disease) can only be rendered useless when replacing neurons lost in the spinal cord.

As aforementioned, there are two main kinds of stem cells used in Alzheimer's disease; these are embryonic and adult stem cells. The two types have got different capabilities in treating of different diseases. Human embryonic stem cells (hESC) started being used in treatment of diseases by researchers in 1998. This was initiated by Dr. James Thomson in the University of Wisconsin where he was heading a group of researchers. In his research with the group, he was developing a technique that could enable them grows and isolates cells. Research on treatment of diseases using embryonic stem cells is still considered to be in the early stages. All stem cells are said to be pluripotent. This means that they develop into every cell, every organ and tissue in the body of a human being. Embryonic stem cells are harvested from the embryo. This is a mass of cells that is the human's earliest stage of development. An embryo that is between three and five days old has several stem cells. Embryonic stem cells are used in the repairing of tissues and cells damaged through injury or disease though at a marginal scale. This is in the process called cell-based treatment.

Induced pluripotent stem cells are ordinary cells that have been specially treated to exhibit properties of embryonic stem cells. These embryonic stem cells properties have advantages without the rejection and ethical problems. Many pro-lifers are against the use of cells from an embryo since for them this is like homicide. Major differences between the embryonic stem cells and the neuronic stem cells are as described below in the table.

Embryonic stem cells

  • They can differentiate to any cell types
  • Have totipotency (a single cell can divide to produce all differentiated cells).
  • They include extra embryo and gammate cells.
  • Are teratogenic (can disturb development and growth of a fetus)
  • After differentiation, they don't match original tissue
  • Ethically, they have a disadvantage due to rejection by pro-lifers

Neuronic stem cells

  • Limited to differention
  • Have multipotency (A single cell can divide to produce multiple different cells)
  • Less teratogenic
  • Proliferate to form a cluster called neurospheres
  • pro-lifers are not against use of NSC

Availability of neural stem cells in the brain has given researchers an impetus to investigate possible neuroreplacement therapies in neurodegenerative disease. Recent techniques in maintenance and isolation of NSCs by use of non-serum culture have made these cells important candidates in therapeutic strategies. In Alzheimer's disease, Neuropathological features create progressive degeneration in cholinergic neurons of the forebrain. Research shows that there is persistence of neurogenesis in aged human dentate gyrus. However, its regulation and role in pathological conditions like in Alzheimer's disease are poorly understood.

Neuropathological features in Alzheimer's disease are characterized by cholinergic neurons degeneration that is located in a rat's cholinergic projection system. This is especially in nucleus basalis of Meynert (nbM) (Moghadam, n.d). A study to investigate production of cholinergic neurons in the embryonic stem cells of the mouse was conducted. There was production of neuronal precursor cells (NPCs) by growth factor mediated selection (Moghadam, n.d). Later, a behavioral assessment on unilateral nbM ibonetic acid-lesioned rats using probe test and Morris water maze revealed there was a behavioral improvement. This was revealed after NPCs transplantation. In this study majority of NPCs had retained neuronal phenotype and about 40% of them had cholinergic cell phenotype (Moghadam, n.d). The final results from this study have important implications because they indicated that transplantation of ESC-derived NPCs from a mouse promote behavior recovery in a mouse model of AD (Moghadam, n.d).

Embryonic stem cells are able to repair cells damaged through a heart attack if they are injected into the heart. A major breakthrough in using of embryonic stem cells was in Mayo Clinic Study where researchers decided to induce heart attack into a rat. Later, embryonic stem cells from a rat were injected into its heart. Damaged muscle tissue was later regenerated by the injected rodent embryonic stem cells and the functioning of the heart was improved. Also, patients with Parkinson's disease have also been treated by being injected with embryonic stem cells. A Parkinson patient lack cells that produce dopamine which is a chemical messenger. Such patients have movements that are uncoordinated and jerky. This results in uncontrollable tremors. In different studies, most researchers have injected rodents with rodent embryonic stem cells into their brains. Dopamine producing cells are generated by injected embryonic stem cells. This makes the rodents improve in their functioning. This is intended to be extended on to humans by the researchers.

Adult stem cells are cells which are undifferentiated found in differentiated cells in organs or tissues. They are able to renew themselves and then differentiate to form specialized cell types of organs and tissues. They have a primary role in maintaining and repairing tissues of where they are found. Adult stem cells that form blood have for a period of 30 years been used in transplant (Scienceblog, 2004). There are few adult stem cells in each tissue compared to embryonic stem cells. Both human embryonic and adult stem cells are advantageous on their use in regenerative therapies. These two types of stem cells differ in the type and number of differentiated types of cells they can become. Because of being pluripotent, embryonic stem cells can turn into any type of cell in the body. On the other hand, adult stem cells have limitations as to the varying types of cells they can differentiate into. There is however some evidence that adult stem cells have some plasticity and thus the number of stem cells that they can differentiate into can increase. In their application to treat diseases, a large count of embryonic stem cells is developed in culture as adult stem cells in mature tissues appear to be rare. Adult stem cells bear an advantage as they can be expanded in culture to be reintroduced in a patient. When cells used come from the patient, they are rejected by the immune system.

Major problem that may be experienced in using embryonic stem cells in cell-based therapies is immune rejection. Since there are few lines of cells in embryonic cells, it is not sufficient to overcome the problem. This call for the use of immune suppression drugs to cure the patient and this might bring adverse effects to him. The embryonic stem cells have even more merits as they can easily be purified. They are immortal and can grow well in culture too. Since they can give rise to any type of cell within our bodies, it therefore means that they can be used in treating any disease (Lovell-Badge, 2001). They however have disadvantages in treating diseases as they appear difficult to control. This is so as the method used in inducing the needed cell type in treating a given disease has to be optimized and defined. For the adult stem cells, their major disadvantage in cell-based therapies is their low count. They are also limited meaning they can't live long in a culture the way the embryonic stem cells do. Adult stem cells are characterized as genetically unsuitable. They sometimes carry genetic mutations for various diseases and may become defective in experimentation.

So far, endogenous neurogenesis has been effectively used to cure several diseases that specifically affect the functioning of the brain. Its effectiveness is seen in Parkinson's disease where there is continuous loss of dopaminergic neurons. Being a neurogenerative disorder, researchers have applied neurogenesis to treat such defects in patients. Researchers have used fetal transplants of dopaminergic cells. This is what has enabled cell replacement therapy which could lead to improvement of symptoms for the affected individuals. Recent research studies have shown that there are neural stem cells that can produce new neurons specifically the dopaminergic phenotype in the brain of an adult mammal. Experimental dopamine depletion in rodents has been used to establish the fact that there is decrease in the proliferation of precursor cells. This happens in subgranular and subependymal regions. To show that neurogenisis is applicable in such cases, selective agonists like D2L receptors were used to restore proliferation which had been affected.

There are plenty of neural stem cells in neurogenic brain parts. These are regions where neurogenesis is continuously happening. Other non-neurogenic regions are also known to have neural stem cells like the striatum and midbrain. In the non-neurogenic regions, it has been shown that endogenous neurogenesis cannot take place during normal physiological conditions (, 2010). Endogenous neurogenesis has thus been used in cell therapies for many neurodegenerative disorders just like in Parkinson's disease where autologous and endogenous neural stem cells are mobilized so that they can replace degenerated neurons. However, despite its effective results in treating several disorders, ongoing endogenous neurogenesis may be affected by several factors. An enriched environment and exercise are some of those factors which determine the effectiveness of neurogenesis. The presence of these two promotes neurons survival. There is also complete integration of newborn cells. Neuronal proliferation is affected and decreased by adverse conditions of aging and chronic stress. A particular central nervous system also affects neurogenesis. This is because neurogenesis only begins after epileptic seizures, bacterial meningitis and cerebral ischemia.

Cajal's "harsh decree" that there is a fixed number of neurons in an adult brain has been disregarded due to numerous observations in order to try and understand whether neurogenesis actually happens in an injured brain. Within subventricular zone and subgranular area of dentate gyrus, it has been observed that neural stem cells (NSCs) undergo neurogenesis (Pecorino, 2010). This has prompted scientists to conclude that survival of differentiated cells together with NCS neurogenesis after neuronal loss contributes to self-repair. This is a process that is stimulated in response to injury of CNS and signaling from astrologia. It has however been found that endogenous neurogenesis by NSCs is not sufficient to compensate for neural loss in aging and central nervous system disorders. It is because of such findings on neurogenesis effectiveness in repairing defective neurons that have made alternative approaches to be sought to restore brains after neuronal loss. One alternative method that has been used is the implantation of progenitor/stem cells. Adult progenitor/stem cells from nonhematopoietic tissues in bone marrow are used to repair damaged tissues where they differentiate into appropriate phenotypes.

In order to understand how stem cells are affected by aging, several studies have been conducted especially using mouse models. In one such study, effects of age on neurogenesis were conducted through monitoring of progressive stages in hippocampal neurogenesis. The main study targets were the age effects on survival, differentiation and proliferation in different age groups of wild mice. It was discovered that net-neurogenesis was drastically reduced in an adult mice compared to young ones. It however remained in a stable position and level in senescent and aged mice. This was attributed to decline in proliferation that comes due to aging. The findings create an insight that in aged mice even though neurogenesis is stable, the neurogenic system has its plasticity reduced in the aged mice. Stem cells in aged mice appear to have reduced in their count and they are also altered (Lanza, 2004). Conclusions from this study were that neuronal stem cells show a defective behavior in an amyloidogenic brain. Moreover, these stem cells have limitations in their ability and function in the aged brain.

When formation of the nervous system is in the early stages, neural stem cells always undergo divisions expanding stem cell pool. Stem cells normally relocate to asymmetric cell divisions after the process of neurogenesis begins. This results in regeneration of new neurons and indefinite increment in population of stem cells. Observation on growth of stem cells for a spell shows that cortical stem cells undergo asymmetric divisions. Frequent mutations results in reduction of asymmetric cell divisions, cortical morphogenesis experience defects and neural progenitor cells have overproliferation. When neural stem cells continue to divide symmetrically, there is a change in their capacity of producing original types of neurons (Shen, 2004). This is followed by diminishing ability to generate new neurons. An aging stem cell has a reduced capacity to produce original types of neurons. It thus translates that capability of a neuron stem cell in making a given type of neuron becomes transitory in development and this eventually becomes totally lost as it continues aging (Zant and Mattson, 2002). This has been cited as one of the major challenges to using neural stem cells in replacement therapies of the Central Nervous System. Neural stem cells expand in vitro so that they can create ample cells to be used in transplantation. After this, they tend to be biased in making of glia. Moreover, they no longer form original cells like principal projection cells. It is now understood as all organisms age, the available pool of neural stem cells in the brain continues to shrink and generation of new neurons is in reduced amount. This is a natural change that correlates with our gradual loss of sensory functions and cognitive ability as people approach the end of their lives.


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