Molecular Neuro-degeneration - Essay Example

Molecular Neuro-degeneration al Affiliation) Key words: Alzheimers disease (AD), Akt/PKB, glycogen synthase, Kinase 3b,neurofibrillary tangles, PTEN. Introduction Alzheimer’s disease is a physical disease affecting the brain and the leading cause of dementia affecting around 496,000 people in the UK alone (Vradenburg 2013). Furthermore this disease affects the brain therefore creating symptoms such as inability to reason and poor judgment and is characterized by the excessive accumulation of extracellular amyloid-b (Ab) that contain defects, and intraneuronal neurofibrillary tangles that are rich in abnormal hyper-phosphorylated tau protein (Dash 2005). Though the signaling events that trigger the pathologies are not understood, it is believed that the sole cause for AD neurogeneration is the accumulation of the lesions. Of late, focus has been shifted studying effects of increased Akt activation, loss of Akt, and altered levels and distribution of phospho-Akt in AD neurons and how the insulin/Akt signaling pathway is targeted by intracellular beta-amyloid. These will help draw the conclusion on treatment of the disease. There are 3 main discussion topics to thoroughly review in this report. These are: 1. PI3 kinase signaling is involved in Aβ-induced memory loss in Drosophila. A team of neuroscientists at Cold Spring Harbor Laboratory (CSHL) has prevented memory loss in fruit flies (Drosophila) caused by brain plaques similar to those found to cause Alzheimers disease in humans. They accomplished this by blocking the cellular signaling activity of a protein. Controversial as it may seem, the role of this protein, PI3 kinase, which was previously thought to have a protective function against the disease it highlighted thoroughly. This study suggests that the peptides of β-amyloid associated with Alzheimers disease directly enhance the activity of PI3 kinase; this in turn causes memory loss and also increasing the accumulation of plaque in the brain (Vradenburg 2013). The Β-amyloid peptides are considered essential for altering a series of cellular signals to proteins such as PI3 kinase thereby causing a wide range of cellular dysfunctions within the brains neurons, hence the impaired brain activity (Dash 2005). The ability of these dangerous peptides to cause signaling havoc and triggering memory loss is still a mystery. This is maybe due to the fact that such studies have been performed in cultured cells and not in living organism Key words: β-amyloid, Alzheimer’s disease, learning and memory, PI3K. 2. PI3K-Akt-mTOR path regulates Aβ oligomer that is induced by neuronal cell cycle It’s a fact that Alzheimer’s disease leads to dementia, causing disabilities and consequently death. Doing a diagnosis of the brain pathology while carefully studying the deposits of the b-amyloid peptide in plaques and intracellular aggregates involving the microtubule associated protein, known as tau, in neurofibrillary attachments may vividly bring out important discovery in AD diagnosis (Vradenburg 2013). Evidently, aberrant neural cell cycle reentry precedes the neurodegeneration, a common observation in AD. In recent studies, findings suggest that soluble, macromolecular assemblies of Ab oligomers are able to inhibit long term potentiation in hippocampal slice cultures thus blocking immunoneutralization of oligomerization. Further studies have revealed that PI3K-Akt-mTOR that signals pathway is controlled directly by exposure to AB and is modified in the brain. In the studies, AB oligomers modulate expression and the amount of insulin receptors (Vradenburg 2013). Secondly, the increase of the levels of the substance phosphorylated Akt substrates, and also the levels of cell cycle are largely located in temporal cortex in comparison to controls. Studies also suggest that in both mouse models transgenic in nature and also patients with the AD condition exposure to AB resulted to an altered mTOR signaling. Furthermore, TOR activation has been attributed to enhancement of tau-induced neurogeneration driving cell cycle and also apoptosis in mitotic neurons. Lastly, the amount of mTOR and the regulations aims to the translation initiation of eukaryotic cells mostly the factor 4Ebinding protein (Perry 2013). In conclusion, the above factors point out that the components of PI3K-Akt-mTOR with the insulin receptor path are all affected in AD and are responsible in with deformed cell cycle relating events. Therefore, these studies draws the conclusion that the composition of insulin receptor plus the PI3K-Akt-mTOR system improves the expression of proteins cell cycle and the neuronal CCEs induction (Klunt 2005). Key words: mTOR, CCEs, phosphorylated Akt substrates. 3. Amyloid-b Interrupts the PI3K-AktmTOR Signaling Pathway That Could Be Involved in Brain-Derived Neurotropic Induced factor Arc Expression in the Rat Cortical Neurons One of the key causes of contribution to the Alzheimer’s disease pathogenesis is the deposition of amyloid-B. Amyloid-B is so dangerous that even its lowest level it interferes with several signaling mechanism necessary for plasticity synapsis which makes learning and memory possible (Rosen 2013). By studying the rat’s cortical neurons, scientists discovered that treatment of fibrillar AB at a non-lethal level was enough to dismantle BDNF induced Arc expression. During a study, BDNF treatment triggered the action of P13-kinase Akt-mammalian target of kanamycin that signals the pathway, the eukaryotic initiation factor 4E phosphorylation joining the protein and p70 ribosomal S6 kinase, the expression of Arc and the dephosphorylating of long eukaryotic factor 2. Consequently, by non-lethal AB pretreatment, it has been noted by there was partial blockage of the effects of BDNF. Further double-immunofluorescence straining of the cortical neurons brought about the fact that the existence of Arc expression and eEF2 dephosphorylating evident (Rosen 2013). The accumulation of senile plaques is one of the pathological detection of Alzheimer’s disease. Constant deposition of the AB leads to neuronal loss leading to impairment and in low levels the AB interferes with signaling cascades necessary for neuron function and thus cognitive disability in the early stages of AD. For a normal brain to be able to learn and memorize, the synaptic plasticity strength is crucial. Furthermore the hippocampal long-term potential triggered by high frequency is the representation model for synaptic plasticity of which two phases are underlined. First of all there is the early phase that is dependent on the modification of existing proteins and the late phase that demands synthesis of mRNAs and proteins (Klunt 2005). In conclusion, a well-defined BDNF signaling cascades involves the P13K which has a role in regulating mTOR function in the protein synthesis dependent late-phase, the extracellular signal-regulated kinase and the phospholipase c-y pathways. In an AD brain, a confused mRNA translation is evident; is a factor that leads to the eventual demise of the persons suffering from the condition (Rosen 2013). Keywords: mRNAs, BDNF, Amyloid-b Discussion Taking all into account, we look at the topics pointed out in the report and try to draw important talking points at each point. These are: PI3 kinase signaling is involved in Aβ-induced memory loss in Drosophila Studies by Ye Feng and Xiao Chuan Wang on the fruit flies engineered to produce human β-amyloid in their brains showed the possibility to hamper the process of AD. As the studies showed, the flies develop several key features of Alzheimer’s including, massive neurodegeneration, age-dependent memory loss, β-amyloid deposits and plaque accumulation. It is possible that LTD enhancement in the β-amyloid-producing flies is because of increased activity of PI3-kinase (Klunt 2005). Measures including reducing the activity through injecting of PI3 kinase-blocking drugs or switching off the gene that encodes PI3 kinase should be employed in reasonable levels. By applying this knowledge to the human brain affected by the AD, it is possible to hinder the progress of the disease by decongesting the β-amyloid and plaques (Vradenburg 2013). In learning the effects ofP13 we are also faced with a condition referred to as "brain diabetes" where brain tissue gradually start become resistant to insulin, therefore impairing brain function further (Vradenburg 2013). Furthermore, insulin is one of the molecules that induce PI3-kinase activity, thereby mediating the cells response to insulin (Rosen 2013). Going by this result, further studies have to be conducted on the Alzheimer’s brains to find out how to withdraw the insulin-resistance as a result of P13 kinase maximum activation (Vradenburg 2013). More so, it might be possible to handle various disease symptoms by targeting PI3 kinase since its activities in the brain are now fully understood. A PI3K-Akt-mTOR pathway that regulates Aβ oligomer neuronal cell cycle process. A study carried out by Toulany et al., demonstrated for the first time that the long term treatment with inhibitors of PI3K performed clinically resulted in a reactivation of the major survival component Akt through an unknown regulatory loop via ERK1/2. In addition to that, the reactivation of Akt efficiently limits the response of the tested tumor cell lines presenting the active K-RAS activity (including both K-RAS mutation and over-expression of K-RAS wild type) to redirect strategies directed against PI3K (Rosen 2013). Through this finding therefore, the described ERK1/2 dependency of reactivation of Akt provides a new and different approach into the underlying mechanisms of resistance accompanying antagonizing strategies of EGFR and PI3K (Klunt 2005). Following this discovery, there are specific hints that may improve how the combination of MEK-ERK1/2 and PI3K inhibitors can efficiently be administered to overcome therapy resistance of tumors presenting constitutively high K-Ras activity. Amyloid-b Interrupts the PI3K-AktmTOR Signaling Pathway That Could Be Involved in Brain-Derived Neurotropic Factor-Induced Arc Expression in Rat Cortical Neurons Going by the discoveries in the report concerning the amyloid-b interruption of the P13-AktmTOR, its evident that the BDNF-induced activation of the mTOR signaling pathway and enhancement of the Ark expressions are greatly reduced by pre-treatment of wortmannin. Since it’s possible to block mTOR-dependent signaling by rapamycin treatment then it is easy to prevent amyloid-b from interrupting the signals pathway (Klunt 2005). Through this way, the synaptic plasticity is restored to capacity hence improved ability to learning and memory span. In conclusion, these studies are bringing closer the discovery of new methods that may be used to suppress the AD condition and with further studies being carried out maybe the permanent solution will be arrived to sooner rather than later (Perry 2013). Conclusion It is evident that no drug has been discovered that could to completely protect neurons; there are two possible approaches to that may come up with the treatment of AD. One approach involves treatment which prevents the onset of the disease through curbing the primary targets and reducing the subsequent pathologies of AD. This way, it becomes possible to slow the disease progression and hence prevention to the development of AD (Vradenburg 2013). The second approach involves the symptomatic treatment; an approach whereby the primary and tertiary symptoms of the AD are declined. Through this approach, reflection to the current state of treatment including the usual treatment the cognitive impairment, the decline in global function, deteriorating performance of activities of daily living and behavioral change ( Perry 2013). When searching for the appropriate treatment strategies, scientists concentrate on the severity of the disease and also the specificity of each individual. Currently the available therapeutic agents are the main target to specific symptoms of AD; the agents such as cholinesterase inhibitors involved in the enhancement of cholinergic neurotransmission and also the inhibiting of acetylcholine degradation within the synapse are the Alzheimer’s disease main treatment (Vradenburg 2013). Going by the report on the role of the involvement of PI3 kinase signaling in Aβ-induced memory loss in Drosophila, the PI3K-Akt-mTOR pathway regulation in Aβ oligomer neuronal cell cycle process and Amyloid-b Interruption of the PI3K-AktmTOR signaling pathway involvement in brain-derived neurotropic factor-induced arc expression in rat scientists can improve their unleash a further superior drug to completely heal the Alzheimer’s disease (Perry 2013). One of the hindrances to the progress of other researches on AD have been due to the fact that most drugs developed show general success in animal specimens but when testing them to human beings, they become less responsive Therefore, it is safe to say that this project is still in its infancy and further studies have to be carried out but at the long run a solution will be arrived upon. References Wirths, O., & Bayer, T. A. (2008). Motor impairment in Alzheimer’s disease and transgenic Alzheimer’s disease mouse models. Genes, Brain and Behavior, 7, 1-5. Vradenburg, G. (2013, November 1). Alzheimers Disease: A Progress Report. Medical Laboratory Observer, 1, 50. Sporadic Alzheimers Disease: the Disease of the Century. (n.d.). StudyMode. Retrieved February 28, 2014, from http://www.studymode.com/essays/Sporadic-Alzheimer’s-Disease-The-Disease-Of-150314.html Sikanovski, D. (1998, June 1). Alzheimers disease: what we know now. (Updates on the disease). Nursing Homes, 1, 50. Rosen, K. M., Moussa, C. E., Lee, H., Kumar, P., Kitada, T., Qin, G., et al. (2010). Parkin reverses intracellular ��-amyloid accumulation and its negative effects on proteasome function. Journal of Neuroscience Research, 88(1), 167-178. Perry, G. (2013). Alzheimers disease advances for a new century. Amsterdam: IOS Press. Klunk, W. E. (2005). Commentary on “Diagnosis of Alzheimer’s disease: Two decades of progress.” Diagnosis of Alzheimer’s disease: Walking a well-paved path. Alzheimers & Dementia, 1(2), 99-100. Dash, P., & Pittman, N. (2005). Alzheimers disease. New York, N.Y.: Demos. Read More