Treating Alzheimers Disease with Vitamin A, C E (ACE)

Treating Alzheimers Disease with Vitamin A, C E ( sorcerer)ACE Alzheimers An accessory strategy of treating Alzheimers disorder with Vitamin A, C E (ACE)ABSTRACTAlzheimers ailment (AD) is a chronic and belatedly progressing neurodegenerative disorder which has become a major concern with regards to health, worldwide. This disorder is characterised by progressive dementia and cognitive line. Pathologically, AD is characterised by the presence of A plaques and tau neurofibrils. However, literature has shown that aerophilic mark is one of the most central lay on the line agent behind the cause of AD. aerobic stress often leads to production of Reactive oxygen Species (ROS), which further amplifys structural and functional abnormalities in neurons of the hit, which subsequently, arranges as dementia and cognitive decline.In order, to trim the aerobic stress, antioxidants drop be of great help. There use up been many evidences that supports the use of antioxidants in the treatment for AD. Vitamins A, C and E are an example of antioxidants that can be used as adjuvants in the treatment of AD. This clause will focus on current literature and will present forward the evidence found advantages of using Vitamin A, C and E as an adjuvant treatment for AD.Keywords Antioxidants, ACE, Adjuvant therapy.INTRODUCTIONA clinical psychiatrist and neuroanatomist, Alois Alzheimer, reported A peculiar severe ailment process of the cerebral cortex to the thirty-seventh Meeting of South-West German Psychiatrists in Tubingen, thus marking the discovery of one of the most evoke pathologies in medicine Alzheimers disease. His invention was based on the observations in one his patient named Auguste D, suffering from operose memory loss, unfounded suspicions about her family, and additional worsening psychological changes. Her post mortem findings further revealed dramatic shrinking of the brain and abnormal deposits in and encircling the nerve cubicles 1.AD has proven to be a operative public health issue, as it consumes a major amount of heath budget in veritable as well as developing countries. AD has become one of the leading causes of dementia in patients less than 65 years, another(prenominal) causes being Lewy body dementia (LBD), frontotemporal dementia (FTD), vascular dementia (VaD) and alcoholic beverage associated dementia 2.United States alone has documented a $200 billion annual expenditure on patients affected by AD. Moreover, one person develops Alzheimers dementia every 68 seconds emphasizing the relative incidence of the disease 3. Dementia can be defined as a chronic progressive disorder attach by memory deficits, personality changes, and impaired reasoning.Results from population-based studies have shown a significant relationship among the veritable risk factors and development of AD. increase risk was shown with an increase in age, fewer years of education, and head trauma. ancestral factors do contribute to the early development of AD increased risk with chromosomal mutations on chromosome 21 (cases of downs syndrome) as it carries the amyloid precursor protein, the presence of apolipoprotein E epsilon 4 allele and the presenilin 1 and 2 genes. The strongest factor place till date are the apolipoprotein E genes located on chromosome 19 which exists in three figures 2, 3, and 4. 2 has been found to reduce the risk, 3 is found to be neutral whereas 4 has been associated with a tremendous increase in risk as well as early development of symptoms (Figure 1) 4.ChromosomeGenes21AMYLOID herald PROTEIN19APOLIPOPROTEIN E14PRESENILIN 11PRESENILIN 2Figure 1. Genetic factors causing a risk to develop AlzheimersAd is difficult to differentiate from other causes of dementia like LBD, FTD and Vad 5. It may present with dysfunction of various fields such as vision, touch voluntary movements, personality deficits and judgemental disorders depending upon the area of the brain affected 6.The National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimers disease and Related Disorders Association (NINCDS/ADRDA) has proposed a diagnostic criteria for differentiating between AD and other known causes of dementia. In compliance with NINCDS/ADRDA , AD is diagnosed if (I) cognitive functions decline progressively over a period of time including/ not including memory harm or (Ia) inability to understand language and verbal commands (aphasia) (Ib) Loss of ability to accomplish tasks out-of-pocket to incoordination of muscles (apraxia) (Ic) Failure to recognise previously known objects and loss of ability to use them(agnosia) (Id) Unable to plan, organise and execute daily chores (II) All in a high place mentioned under I do get progressively deteriorated with time (III) Other known causes of dementia as well as cognitive deterioration must be eliminated 6,7.Neurofibrillatory tangles and extracellular amyloid plaques have been the sign histopathologic al findings associated with AD. Recently several other features have been recognised which include degeneration of nervous synapses, aneuploidy and loss of neurons in the hippocampus. Despite the recent inventions, presence of extracellular amyloid plaques and intracellular NFT have been taken into account as the main histopathological criteria for establishment of AD 8. Among all the different hypothesis, A cascade has been the most accepted. Previously, a mutation in beta-Amyloid Precursor Protein (APP), which contributes to the normal function of neurons and cerebral development, was thought to be the sole culprit since the ingathering of A proteins had lead to the pathogenesis of AD 9. Eventually, mutated presenilin genes (both 1 and 2) have been discovered to play a division in the shaping of A pools 10. But the exact apparatus underlying how A aggregation contributes to the pathophysiology of AD by and large remains unclear. Formerly, toxicity of neurons was believed to be caused by intracellular plaques. But recent data has suggested the role of intracellular A proteins, which do not become sequestered into the extracellular plaques, as the toxic triggers stimulating the feeler of AD 11. Recently, it has also been shown that intracellular accumulation of A proteins precedes the brass of extracellular A protein plaques and NFT formation 12. The role of intracellular A protein in the progression of AD has also been demonstrated in recent experiments on transgenic mice. Results of these experiments indicate that increased deposits of A proteins within the cells are associated with accelerated cell death 13.Other of the essence(predicate) causative factors in the development of AD include aerophilic stress and Reactive Oxygen Species (ROS) 14. talent to aerophilous prostitute is due to several factors which include relatively lower levels of antioxidants, significantly higher levels of polyunsaturated fatty acids, (these fatty acids rapidly fal l prey to ROS), the presence of metallic ions and high oxygen engagement 15. Oxidation have been prove to be fatal for several constituents of the cells including carbohydrates, lipids, proteins, RNA and DNA 16. Indirect mechanisms do play a vital role in the damaging process. Oxidation has been proven to accelerate the conceptualisation of inducible nitric oxide (iNOS) and accentuate the action of neural NOS (nNOS). This leads to increased production of nitric oxide (NO). NO is known to interact with super oxide anions thus forming a highly unstable peroxynitrite anion. These transient molecules exerts their rigs mainly on sulfhydryl groups of cells. 17. The ideal process has been visualized in figure 2. Figure 2. Nitric Oxide PathogenesisIn addition to the indirect mechanisms, oxidative stress alters the protein structure. Impaired proteins are known to accelerate oxidative damage, thus proven to be interrelated. ROS causes the protein to be change leading to a modified st ructure and causing them to be dimerized and aggregative 18. Thus the oxidised protein which is both structurally and functionally abnormal gather as inclusions within the cytoplasm of the neurons, seen in the form of NFT (tau aggregates) and A plaques 19. Alternatively, A plaques can also lead to the increased production of ROS. The entire process has been depicted in figure 3.OXIDATION ALTERED PROTEIN STRUCTURE CYTOPLASMIC INCLUSIONS DIMERISATION AGGREGATIONFigure 3.Displaying Correlation between Oxidation and Protein Dimerization, thus forming a Vicious CycleA (1-42) is an abundant species of A proteins seen in AD 20. A (1-42) peptides is known for its toxicity which can be attributed to a residue of methionine at position 35 21. Oxidation of methionine contributes to the formation of methionine sulfoxide, which generally leads to irreversible oxidisation and subsequently, forming methionine sulfone 22. Methionine sulfoxide reductase (MSR) can even help the reduction of methi onine sulfoxide into methionine 23. However, the activity of MSR is also observed to be impaired in AD 24. Methionine peroxide plays an important role in oxidative stress and toxicity caused by A (1-42) peptides. The lone-pair of electrons present on the S atom of methionine undergoes oxidation of one atom and as a result, sulfuranyl radicals (MetS.+) are generated 21,25. Sulfuranyl radicals are known to trigger the generation of other ROS like sulfoxides and superoxides by interacting with molecular oxygen 26.The reason behind this intense oxidative damage could be attributed to the relative absence or decreased function of different antioxidant mechanisms of the body. Glutathione is one of the major antioxidant which can shelter the brain tissues by causing detoxification of damaging ROS 27. One of the main reasons of increase in oxidative stress in AD is the decreased glutathione levels in the brain 28. The other members of the cellular antioxidant mechanism which plays a impor tant role includes superoxide Dismutase (SOD) and Catalase (CAT). SOD is an antioxidant which is responsible for converting toxic superoxide ions into far less toxic heat content peroxide 29. CAT evolves this reply in to one step further and turns hydrogen peroxide into wet 30.Investigations have revealed that the levels of SOD and CAT decline in patients with AD 31. Glutathione reductase (GR) and Glutathione peroxidase (GPx) represent the other crucial split of the cellular defence mechanism which acts against oxidative stress. GPx is responsible for the metabolism of hydrogen peroxide and lipid hydroperoxides 32 and GR accelerates the reaction which helps in the regeneration of Glutathione (GSH) 33. In total, the combination of an oxidative stress with above mentioned cellular defence mechanism against ROS, leads to the pathogenesis of AD. The pathogenesis of Alzheimers disease is mentioned in Figure 4.Figure 4. Pathogenesis of Alzheimers disease (MG Microglia AS Astrocyte AP Amyloid protein beta NFT Neurofibrillary tangles)ACE ALZEIHMERS VITAMIN A, C E (ACE) THERAPY ROLE OF VITAMIN AVitamin A and beta carotene have been shown to have multiple benefits for batch suffering from AD. non-homogeneous studies have found that patients suffering from AD have significantly lower levels of Vitamin A level and beta carotene in their CSF as well as blood 34. The development of neurodegenerative disorders has shown to be influenced by Vitamin A and beta-carotene. Vitamin A plays an active role in neuronal development both in early life and in the adult nervous system. It protects and assists in the regeneration of neurons during recovery from neurodegeneration 35.Inhibition of formation and destabilization of A fibrils is an additional effect of Vitamin A and beta-carotene 35. Since oligomerization of A fibrils is an important mechanism contributing to neuronal toxicity in AD, Vitamin A addendum has been shown to decrease the aggregation and oligomerization of A40 and A42 fibrils 36. It has also been shown that Vitamin A and beta carotene decrease the decline of cognitive function in AD. Moreover, higher levels of these vitamins have been associated with better memory performance and spatial learning in these patients 3436.ROLE OF VITAMIN CVarious studies both in vivo and in vitro have shown to have significant effect in the brain due to decreased levels of vitamin C. Decreased plasma levels despite adequate intake in patients further confirmed the printing of protective effects of vitamin C in the spectrum of neurodegenerative diseases 37. Hence, it can be proved that oxidative stress induces damage in AD and protection against this stress is offered to a certain layer by antioxidant vitamins. The progression of AD is altered by Vitamin C by interfering with various different aspects of pathology.Numerous studies, both in-vivo and in vitro, have shown that Vitamin C can decrease oxidative stress. The structural progression of AD is prevented by Vitamin C by hindering the oligomerization of A peptides 38. Brain injury induces oxidative stress and reduces the level of antioxidants like vitamin C and SOD. Vitamin C supplementation improves the level of SOD, which consecutively helps to decrease oxidative stress and subsequent brain injury 39.It has been suggested that even without additional supplementation, a normal intake of Vitamin C can have a neuroprotective effect in patients with AD. Cognitive decline in AD patients has shown to decrease is patients taking adequate Vitamin C 40. In addition, results from a prospective observational study (n=4740) over a period of 3 years have shown that additional supplementation with antioxidant vitamins like vitamin C and E may be associated with both decreased incidence and preponderance of AD 41.ROLE OF VITAMIN EVitamin E represents a cluster of 8 antioxidants composed of 4 tocotrienols and 4 tocopherols. It has been reported that there is a greater risk of neurodegen erative disorders like AD and Mild Cognitive Impairment (MCI) with lower plasma levels of vitamin E. Additionally, the level of vitamin E metabolic products (5-nitro--tocopherol etc.) is shown to increase significantly in AD and MCI 42.Deficiency of Vitamin E can lead to the damage and destruction of neurons and has been implicated in cases of cerebellar shrink 43. Vitamin E is a potent antioxidant which can delay the progression of AD at several levels. Increased oxidative stress induced by A plaques is known to be a risk factor for neuronal death and ensuing brain injury in AD. Vitamin E behaves like a magpie for these free radicals and therefore, is neuroprotective. 44.Vitamin E also provides protection against AD via various other methods. For example, the 12-lipoxygenase pathway leads to glutamate-induced neuronal cell death by inflammation. Vitamin E can reduce this inflammation induced neuronal death 45. Furthermore, usance of vitamin E has been linked with the regeneration of SOD, levels of which are shown to decline in AD 39. Among the different forms of vitamin E, the greatest degree of protection against AD is provided by -tocopherols and -tocopherols 46.A population-based cohort study of 5395 individuals was conducted to evaluate the efficacy of dietary supplementation of antioxidants to provide protection against AD. Among all the antioxidants used, results showed that the most significant degree of protection (p=0.02) against dementia and AD was provided by Vitamin E 47. Moreover, supplementation of 30 International Units of alpha-tocopherols can act as a valuable adjuvant in the treatment of various neurodegenerative diseases, including AD 48.ConclusionAlzheimers disease represents one of the most significant age-related neurodegenerative disorders. Oxidative stress is one of the most important mechanisms involved in the development and progression of this condition. In order, to curb the oxidative stress, antioxidants can be of great help. Th e use of antioxidant vitamins A, C and E as adjuvant therapy for AD has always been given consideration. 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