Glial Activation And Proinflammatory Cytokines In APP / Ps1 Transgenic Mice Case Study

As AD is a progressive disease with no currently known cure, all current treatments are aimed at slowing the progression of the disease; these treatments have been available since 1993 (Geldmacher et al., 2011). The desired

2010). The neuroinflammation is an early, non-specific immune reaction to tissue damage or pathogen invasion (Lee et al. 2010). Inflammation of the central nervous system (CNS) is characterized by increased glial activation, pro-inflammatory cytokine concentration, blood-brain-barrier permeability, and leukocyte invasion (Lee et al. 2010). Microglia are cells that support and protect neuronal functions (Lee at al. 2010). They act as the first and main form of active immune defense that orchestrate the endogenous immune response of the Central Nervous System. The microglia play a central role in the cellular response to pathological lesions such as Aβ. Aβ can attract and activate microglia, leading to clustering of microglia around Aβ deposits sites in the brain (Lee et al. 2010). Even though microglia have neuroprotective functions, neurotoxic mechanisms which involves continuous activation of microglia and toxic factors are released by microglia, which may lead to neuroinflammation (Lee et al. 2010). Astrocytes (star-shaped glial cells) are the most abundant cells in the brain and are located in the brain and spinal. Astrocytes have various functions such as: biochemical support of endothelial cells of the BBB, supplying nutrients to the nervous tissue, maintenance of extracellular ion balance, and healing the brain and spinal cord following traumatic injury (Lee et al., 2010). Chemokines are released by astrocytes which attract microglia and they further express proinflammatory products, thus increasing neuronal damage in the pathogenesis of AD (Lee et al., 2010). Astrocytes play a critical role in Aß clearance and degradation, and they also provide trophic support to neurons forming a protective barrier between Aß deposits and neurons (Wyss-Coray et al., 2003). Neurons contribute to the production of

Association). While current research efforts have looked to determine how and why AD is caused, the pathogenesis of the disease in patients is

In general, each neuron releases a single type of neurotransmitter. Neurons that release the neurotransmitter acetylcholine are called cholinergic neurons and degeneration of cholinergic neurons in the brain are associated with Alzheimer’s (Sherwood). Drugs classified as short-term cholinesterase inhibitors are used to treat Alzheimer’s because the drugs prolong the effect of acetylcholine. There are special cells called microglia that are associated with Alzheimer’s disease as well. Microglia are immune defense cells in the CNS (central nervous system) or brain and spinal cord. The remove foreign and degenerate material in the CNS. Overactive microglia appear to be involved in a variety of inflammation-related disorders like Alzheimer’s (Sherwood). Inflammation is triggered by the body’s immune system and is a factor that plays in the progression of the disease (Alzheimer’s Disease & Dementia).

FINDING GENES Causes of AD include extracellular neuritic plaque and intracellular neurofibrillary tangles. The plaque has amyloid-[beta] peptides (Tanzi, 2001). A protein called tau makes tangles

Also, along with Alzheimer’s, there are other diseases such as Parkinson’s which show no improvement and are a huge liability to the health care system. A lot of research is ongoing since ages but no drug is so far available which can cure such a disease. AD occurs due to progressive loss of the neural cells, which causes loss of memory, which might end up as fatal. Recent advances in the research have found the AD occurs to loss of mitochondrial function and mis-folded proteins. Currently six drugs have been approved in the United states for AD. All the drugs have shown moderate improvement in behavioral and functional measures in the

Multiple Sclerosis (M.S) is a chronic autoimmune, inflammatory disease of the Central Nervous System (CNS) that leads to a variety of disabilities, including: asthenia, lack of coordination, abnormal vision, cognitive changes, and sexual and urinary dysfunction(1). M.S pathogenesis involves a complex process of the activity of macrophages and micro-glial cells that leads to differentiation of specific neural Th1 lymphocytes (Myelin auto reactive T-Cells) and secretion of pro-inflammatory cytokines in the CNS. Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease, characterized by inflammation of central nervous system (CNS) injury. This disease is an animal model of multiple sclerosis in human (2). In EAE, CD4+ lymphocytes call macrophages to the central nervous system, subsequently they are activated against microglia cells, which lead to demyelination of neurons (3, 4). EAE can be induced by injection of central nervous system proteins, such as basic myelin proteolipid protein derived from CNS proteins, to animals such as monkeys, pigs, rats and mice (5, 6). Recently, the role of Th2 cytokines in therapy and control of EAE as a potential treatment for M.S has been accepted. Following information suggest that immune modulators, especially those that lead to suppress Th2 environment, can be potential treatments for M.S(3). Many studies have shown that M.S is a Th1 lymphocyte-dependent autoimmune disease. There have been significant

Alzheimer's Disease is a condition that affects 50% of the population over the age of eighty five, which equals four million Americans each year. It is becoming an important and high-profile issue in today's society for everyone. There are rapid advancements being made in the fight against this disease now more than ever, and the purpose of this essay is to educate the public on the background as well as the new discoveries. There are many new drugs that are being tested and studied every day which slow down, and may even halt the progress of the disease.

Microglia, in the same way as vascular cells, can bind to Aβ resulting in an amplified production of cytokines, glutamate and nitric oxide (6, 7). Some studies suggest that chemokines can recruit monocytes from the peripheral blood into plaque bearing brain.(8) Related to this neuroinflammation are the alterations of type I and type II Interferon (IFN) levels in AD mice model, PDGFB-APPSwInd (J20), where an enhanced type I IFN signaling at the brain barriers and hippocampus, and decreased type II IFN response, only at the barriers were observed.(9) Of interest the blockage of IFN type I response at the central nervous system is able to partial revert the cognitive decline in aged mice.(10) However the role of this blockage on an AD mice model is still

This specific gene codes for amyloid beta peptides. The amyloid beta peptides are found in the plaques associated with AD and also in the neurofibrillary tangles. Accumulation of this peptide may cause AD. There is usually too much accumulation of amyloid beta in the brain and not enough clearance. The build up then causes the plaques and tangles. It is believed that a missense mutation in the precursor for this peptide is what causes an imbalance between accumulation and clearance. Also, when the amyloid beta forms deposits in the neurons, it is believed to stimulate activity of microglial cells. When these cells are stimulated, it causes the production of more amyloid beta, accounting for the progression of the disease. This theory is known as the amyloid beta cascade hypothesis. Although there are many supporters of this theory, there still is not enough evidence to prove it and there is some evidence against it. Firstly, there is not a mutation in the amyloid gene that increases the risk of familial AD. Amyloid beta has also been shown to be non toxic, so it alone can not account for the death of neurons in the brain associated with AD. However, the stimulation of the microglial cells also results in the production of tau proteins, which when in excess, may be the cause of neuronal death. Also, the microglial activation might cause the release of other neurotoxic molecules, such as IL-1b, IL-6, TNFa, nitric oxide, and many other

Glial cells are the most numerous cells in the brain, outnumbering neurons nearly 3:1, although smaller and some lacking axonal and dendritic projections. Once thought to play a subpar role to neurons, glial cells are now recognized as responsible for much greater functions. There are many types of glial cells, including: oligodendrocytes, microglia, and astrocytes. Oligodendrocytes form the myelin sheath in the CNS, by wrapping themselves around the axons of neurons. Their PNS counterpart, Schwann cells, are also considered glial cells. This sheath insulates the axon and increases the speed of transmission, analogous to the coating on electrical wires. Microglia are considered to be “immune system-like”; removing viruses, fungi, and other wastes that are present. Astrocytes, however, are considered to be the most prominent. Their functions span throughout the brain, including, but not limited to: the synchronization of axonal transmission via G-protein-coupled receptors, blood flow regulation via the dilation of blood vessels, and the performance of reactive gliosis in conjunction with microglia. Both astrocytes and oligodendrocytes develop from neuroepithelial cells. Other types of glial cells include Radial glia, which direct immature neuron migration during development.

Alzheimer’s disease (henceforth: AD) though has four approved drugs, yet still treatment remains ineffectual and as such continues to pose a great burden to families of affected individuals, societies as well as developed countries. The complexity of the pathogenesis of AD makes it difficult to ascertain its cause along with effective treatment.

AD is the most common devastating neurodegenerative disorder and the cause of dementia affecting mainly elderly population. It is found that 24.3 million people have dementia today. The cause of AD is still controversial but the main pathology is deposition of Amyloid Plaques and neurofibrillary tangles in the cerebellum. The most of currently existed medications aim to clear these depositions to delay the progression of the disease but it can't completely cure it.The pathology of AD starts to develop over a decade prior to the symptoms, so we have to direct our efforts to detect the disease early and control the modifiable risk factors to prevent the development of AD later in old age or delay the onset of AD by 5-10 years. The most important

and Mattson, 2011), and impairments of axonal transport and mitochondrial functions (Decker et al., 2010; Querfurth and LaFerla, 2010; Sheng and Cai, 2012). In addition, several lines of evidence suggest that Aβ regulates neuronal and synaptic activities and that its accumulation in the brain causes aberrant network activity and synaptic depression (Palop and Mucke, 2010). Impairments of inhibitory interneurons and aberrant stimulation of glutamate receptors result in excitotoxicity, and play important upstream roles in this pathogenic cascade. These impairments also lead to a positive feedback loop, where aberrant neuronal activity augments Aβ production, which in turn leads to further neuronal damage (Palop and Mucke, 2010; Bero et al., 2011; Verret et al.,

We found positive effects of xamoterol on cognitive function in mouse models of DS (Salehi et al., 2009). While the molecular mechanisms behind this effect are yet to be elucidated, it has been shown that chronic treatment of adult 5XFAD mouse model of AD with xamoterol can normalize gene expression for a number of inflammatory factors including CD74, CD14 and TGFβ in the cortex. In addition, the similar effects were found on immunoreactivity for amyloid (6E10) and early neurofibrillary degeneration in these mice {Ardestani, 2017 #134}.