Alzheimer s Disease in Adulthood - Research Paper Example

?Alzheimer ’s Disease in Adulthood Introduction Alzheimer's disease is a degenerative disease of the brain that causes dementia. It is an incurable condition and merits importance because it is the most common cause of dementia. The characteristic feature of the disease is disruption of cognition and behavior of the individual. It is a public health problem and often diagnosed after 65 years of age (Anderson, 2010). Individuals with this problem are irritable, confused and have swings in mood. They can be aggressive and have breakdown in language. They usually have long term loss in memory and fail to acquire new memories. The condition occurs due to accumulation of a protein called amyloid in various parts of the brain. The clinical presentation, age of onset and course of the disease is different for different individuals. The exact cause of the disease is yet unknown. In this essay, Alzheimer's disease in late adulthood will be discussed through review of appropriate literature. The disease: clinical presentation and course Alzheimer's disease (AD) is a common degenerative disease of the brain that leads to dementia (Anderson, 2010). Infact, it is the most common cause of dementia and is incurable. The disease is an acquired condition in which there is impairment of cognition and behavior of the individual that is severe enough to disrupt normal occupational and social functioning of the individual. AD is a major public health problem associated with significant morbidity, impairment and economic consequences (Anderson, 2010). More often than not, the disease is mainly diagnosed after 65 years of age, although, an early-onset variety of AD does exists which presents much early. According to Brookmeyer et al (2007), 1 in 85 people in the world are likely to suffer from AD by 2050. The course of the disease is different for different individuals and thus is the prognosis. The most common early symptom, which is often ignored as an aging feature or stress consequence is the lack of ability to acquire new memories. Other symptoms include changes in cognition and behavior of the individual like irritability, confusion, aggression, mood swings, breakdown in language, withdrawal and long term loss of memory. As the age advances, various functions of the body are gradually lost, terminating in death. AD imposes severe burden on the caregivers and can influence various aspects of the life of the caregiver detrimentally. Diagnosis of AD is mainly established through tests for cognition and assessment of behavior. Brain scan is often used as an adjunct to establish the diagnosis. The mean life expectance of the individual following the diagnosis is about 7 years (Molsa et al, 1995). Causes of Alzheimer’s disease The exact cause of AD is still not understood well and there is no treatment which can either cure the disease or prevent the progression of the disease. Even the prevention of the disease is unknown although some researchers are of the opinion that regular exercise, balanced diet and mental stimulation prevent AD (Anderson, 2010). There is some evidence to tell that AD is associated with tangles and plagues in the brain. Previously, it was hypothesized that decrease in the synthesis of acetylcholine causes the disease. This is known as the cholinergic hypothesis. Infact, several treatments for AD were based on that. However, since patients did not respond well to those treatments, the hypothesis could not be maintained. Subsequently, the amyloid hypothesis was developed, according to which, deposits of amyloid beta were the cause for development of the disease. The gene for amyloid beta precursor protein has been identified on chromosome 2. The fact that patients with Down syndrome having an extra copy of this gene definitely develop this disease is an extra support to this hypothesis. There is some evidence to show that APOE4, one of the risk factors for AD, contributes to increased deposition of amyloid in the brain, much before the onset of symptoms. From these facts, it is evident that deposition of amyloid beta is the main cause for development of AD. Research in mice has shown that transgenic mice acquired with mutated APP gene of humans develop plaques of fibrillar amyloid which are similar to those found in human AD brains (Lalonde et al, 2002). Amyloid beta appears in several forms and it has been suspected that the oligomers of the non-plaque amyloid beta are the primary pathogenic agents in AD. This is because; a particular vaccine that was developed to clear the plaques of amyloid in the brain failed to prevent the development and progression of AD (Holmes et al, 2008). Thus, it has been thought that some specific forms of the amyloid beta cause the disease. These oligomers are now considered as toxic forms of amyloid beta and also known as amyloid-derived diffusible ligands (ADDL). It has been proposed that ADDLs bind to the receptors on the surface of the neurons, causing a change in the structure of the synapse and thus disrupting the communication between neurons. Recent research by Nikolaev et al (2009) has identified N-APP, which is actually a fragment from the N-terminus of APP, as the culprit. The researchers proposed that this peptide binds with death receptor DR6, a neuronal receptor and triggers a cascade of events that culminate in self-destruction. Previous research has identified the rampant presence of DR6 in brains of those afflicted with AD (Nikolaev et al, 2009). Currently, it has been thought that AD is a proteopathy, in which there is accumulation of amyloid beta and tua proteins which lie abnormally folded. Thus, AD is considered as a protein misfolding disease. The plaques in AD consist of small peptides, the amyloid beta, each consisting of 39- 43 aminoacids. Amyloid beta is a result of fragmentation of APP which is a transmembrane protein in the neurons of the brain. Infact, APP is very critical for the survival, growth and repair of neurons (Priller et al, 2006). Along with amyloid deposition, there is also deposition of tau protein. Tau is an important protein essential for stabilization of microtubules. In this essay, however, only the role of amyloid in the pathogenesis of AD will be discussed. Biological function of APP and its proteolytic fragments According to the amyloid hypothesis of Alzheimer's disease (AD), various changes in either degradation or generation of amyloid-beta-peptide (Ab) are the most important aspects of pathogenesis of AD. Beta amyloid is a product of amyloid precursor protein (APP). The proteases, beta-secreatase and gamma-secretase act on APP to form beta amyloid (Wilquet and deStrooper, 2004). Beta amyloid accumulates in the tissue of the brain in patients with AD and forms amyloid plaques which are responsible for the patho-clinical manifestation of the disease (Hare, 2006). While amyloid is deposited within the parenchyma of the brain, tau is deposited within the neurons in the neurofibrillary tangles (Winklhofer et al, 2008). Biologists consider APP as a membrane-anchored receptor. Its ligand, APP695 was identified only recently. One of the neuronal glycoprotein, F-spondin, which functions in the axonal path finding and regeneration of neurons binds to APP. This interaction inhibits the enzyme b-secretase and also leads to transactivation in cultured cells that are dependent on the APP intracellular domain (AICD). Thus, it is evident that the binding of these ligands is principle in the regulation of the cleavage of APP. However, even now, it is not clear as to where the APP acts as a receptor in the cell. While the interaction between APP and F-spondin is thought to occur on the surface of the cell, there is some evidence to show that APP acts as a receptor even in the axonal transport vesicles intracellularly, where in it interacts with the cytoskeleton of the microtubule and kinesin, and transports the cargo to the synaptic terminal. APP also interacts with a large protein related to low density lipoprotein (LRP) through their domains in the cytoplasmic region. Both LRP and APP bind to a specific adaptor protein Fe65 and this interaction increases the proteolytic processing of ARP. Once the ectodomains are removed, both APP and LRP become substrates for gamma-secretase and the cytoplasmic domains of the end-product become involved in gene regulation. Some research points to the fact that the intracellular domain of the LRP regulates gene transcription negatively through the AICD-Fe65-Tip60 complex (Wilquet and deStrooper, 2004). It is a known fact that the ectodomain of APP that is secreted, APPs, has the capability to induce growth promotion of fibroblasts. Infact, current research has identified several APPs695-binding sites in the subventricular zone of brain. It has been thought that APPs695, along with epidermal growth factor (EGF), increases the proliferation of progenitor cells in the subventricular zone of adult brain. Such an activity is however, not seen in the dentate gyrus of the hippocampus. Thus, APPs has been thought to be a growth factor, although its receptor and the pathways that mediate the function are yet to be identified (Wilquet and de Strooper, 2004). Along with APPs, Ab and p3 peptides also are secreted into the extracellular system of the brain. It is yet unknown whether p3 has a role to play in amyloidogenesis since it is strongly hydrophobic. On the other hand, there is enormous research about the implications of Ab peptide which is neurotoxic. Ab peptide is definitely incriminated in the process of neurodegeneration in the brains of those with AD. But the mechanisms through which Ab peptide causes the disease is yet unclear. Infact, several mechanisms have been proposed in this regard. There are both longer and shorter forms of beta amyloid. The longer forms have about 42- 43 amino acids and are more insoluble. They have a propensity to form a fibrillar soluble oligomer that has toxic effects on the brain cells (Hare, 2006). Current research has concentrated on the oligomeric forms of Ab peptides. The oligomers can be either dimers, timers, tetramers or even dodecamers (Winklhofer et al, 2008). These forms have been thought to interfere with long term potentiation of hippocampus and cause synaptic dysfunction in AD. However, one thing that has perplexed the researchers is the fact that Ab peptide is naturally secreted continuously even under normal physiologic conditions and if such a protein can actually induce pathology. There is enough research to support the fact that decrease in the levels of Ab peptides in the brain affects the viability of the neuronal cells in the brain, but not the non-neuronal cells. Modulation of the processing of APP through stimulation of the neurones leads to increased production of Ab peptides and depression in the transmission at synaptic level. It has been proposed that such an effect on synaptic transmission is actually mediated by the oligomeric forms of Ab peptide (Wilquet and deStrooper, 2004). Several researchers have supported the postulation that intracellular gamma-secretase proteolytic fragment AICD has a role to play in the nuclear signaling, although, there is no evidence to back this hypothesis. AICD has been thought to exert its effects through the AICD-Fe65-Tip60 complex when in membrane bound state itself, through recruitment and activation of Fe65. When this is subjected to gamma cleavage, both activated Fe65 and AICD are released. However, only activated Fe65 becomes involved in the transcription of the transactivating gene. One major difficulty in ascertaining the role and function of AICD is the use of assays which are heterologous (Wilquet and deStrooper, 2004). The toxic mechanism of beta amyloid is probably mediated through redox-active transition metal ion coordination which, ultimately lead to reactive oxygen generation and develop the propensity to interact with lipid bilayers (Barnham et al, 2006). The metal ions involved in this process are mainly copper. Protein Folding and Aggregation Beta amyloid occurs as several species and each species has a different specific length. The 40 amino-acid species are abundant, but is actually benign. The 42-aminoacid species is toxic, because it aggregates faster and hence induces pathology (Winklhofer et al, 2008). During the process of deposition, the beta amyloid protein folds improperly resulting in the instability of several membrane proteins, thus contributing to the disease. Proteins which are misfolded, preclude escape from the endoplasmic retinaculum, they fail to enter the normal secretory pathway and they do not function normally (Hare, 2006). Several experiments have proven the fact that events which occur during the early phase of maturation of APP in the endoplasmic retinaculum are actually critical in the processing of APP. APP is associated with gp78 (BiP) and calnexin in the endoplasmic retinaculum. When the interaction between APP and gp78 is prolonged, the reduced ATPase activity slows the formation of beta amyloid. Intermediates which are formed during the early stages of APP maturation interact with chaperone proteins located in the endoplasmic retinaculum. Presenilins also are located in the endoplasmic retinaculum and mutations of the genes coding these proteins enhance the formation of beta amyloid in the endoplasmic retinaculum. These mutations also cause down regulation of the response to unfolded protein, thus causing an increase in the deposition of unfolded protein (Hare, 2006). Misfolding of amyloid protein mainly occurs because of the presence of 10 residues of cysteine in the amino terminal folded domain of APP and also because only 3 disulfide bonds exist which contribute to reshufling of disulphide bonds (Hare, 2006). Amyloid fibrillogenesis It has been thought that the formation of amyloid fibrils is driven partially by hydrophobic interactions. Thus, beta amyloid peptides which have 2-3 more additional aminoacids which are hydrophobic at the C-terminal end are more amyloidogenic. Rapid aggregation of beta amyloid occurs when beta amyloid adopts to beta sheet conformation. Such a conversion is catalysed by different factors like chaperone proteins: amyloid-P component and APOE, metal ions: aluminium an zinc, changes in pH, increased concentration of beta amyloid and oxidative stress. 2 steps have been identified in the fibrillogenesis of beta amyloid. They are nucleation and elongation. The central hydrophobic region of the beta amyloid plays an important role in the modulation of formation of amyloid (Soto, 1999). Implications for practice and research Several strategies have been developed to reduce the progression of AD. Development of these strategies has been possible through the understanding of the generation, production, agrregation, formation and trafficking of the beta amyloid and its precursor, the APP (Soto, 1999). Certain gene therapy techniques have been developed to prevent the expression of APP and examples of these techniques are ribozymes that are genetically engineered and antisense oligonucleotides. This is however, yet in the development stage. Another strategy which has been studied is the alteration of the processing of APP. It is a well known fact that beta amyloid develops from APP mainly through 2 separate proteolytic cleavage events by the enzymes beta secretase and gamma secretase. It has been thought that inhibition of production of these enzymes or, on the other hand, activation of the production of non-amyloidogenic APP decreases the concentration of beta amyloid, thus slowing the formation of amyloid. However, this has not been possible because of lack of clear understanding of the mechanism of clearance of beta amyloid (Soto, 1999). The third strategy which has been studied to treat AD is the prevention of the neurotoxicity of amyloid. Research has shown that only fibrillar amyloid aggregates of AD induce neurodegenerative changes and not non-fibrillary aggregates. However, the exact mechanism of neurotoxicity of beta amyloid is yet unclear. While some have proposed that toxicity occurs due to increase in the intracellular levels of calcium ions, some others have opined that amyloid deposition impairs the redox activity in the mitochondria, leading to an increase in the levels of free radicals. Formation of ion channels also has been one of the proposed mechanism of neurotoxicity. There is some evidence to show that interaction of the amyloid beta deposits with specific receptors in the cells causes activation of the signal transduction, leading to neuronal toxicity. Since there is no identified single mechanism, no specific therapy could be developed (Soto, 1999). The fourth strategy proposed for treatment of AD is the inhibition of formation of beta amyloid fibrils. It is a well known fact that aggregation of beta amyloid and deposition of amyloid in the cerebral parenchyma are the first steps in the development of AD. However, since there is insufficient knowledge about the specific species of beta amyloid that is neurotoxic, no definite therapies could be developed in this regard. Currently, research is going on to inhibit the formation of amyloid by using beta sheet breakers which bind to 13- 19 residues of beta amyloid. However, this is still in research stage (Soto, 1999). Other strategies which are being tried include inhibition of cholesterol synthesis, immunological approaches, increasing beta amyloid clearance and preventing expression of APP (Wolfe, 2002). Conclusion Beta amyloid deposition has been incriminated in the pathogenesis of AD. The protein is an end-product of double cleavage from the precursor, amyloid precursor protein. The formation of beta amyloid occurs at several levels in the cell and secretory pathways and influenced by genes, mutation of genes, conditions of the cell, oxidative stress and processing pathways. Beta amyloid deposits in the form of plagues and fibrillary tangles which are neurotoxic. The protein folds and prevents solubility and enhances neurotoxicity through several mechanisms. The discovery of the structure of amyloid protein and the mechanisms of its generation has provided scope for development of treatments against the progression of AD. However, until now, no specific treatment or preventive measure has been developed because of lack of understanding of the clear mechanism of pathogenesis of the disease. References Anderson, H.S. (2010). Alzheimer Disease. Emedicine from WebMD. Retrieved on 26th April 2013 from http://emedicine.medscape.com/article/1134817-overview Barnham, K.J., Cappai, R., Beyreuther, K., Masters, C.L., and Hill, A.F. (2006). Delineating common molecular mechanisms in Alzheimer's and prion diseases. J. Neurosci., 26 (27), 7212–21. Brookmeyer, R., Johnson, E., Ziegler-Graham, K., Arrighi, H.M. (2007). 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