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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
21

Altered proteins in the aging brain

Elobeid, Adila January 2016 (has links)
The classification of neurodegenerative disorders is based on the major component of the protein aggregates in the brain. The most common altered proteins associated with neurodegeneration are Hyperphosphorylated tau (HPt), beta amyloid (Aβ), alpha-synclein (αS) and transactive response DNA binding protein 43 (TDP43). In this study we assessed the incidence and the neuroanatomical distribution of proteins associated with neurodegeneration in the brain tissue of cognitively unimpaired subjects. We demonstrated the early involvement of the Locus Coeruleus (LC) with HPt pathology in cognitively unimpaired mid aged subjects, a finding which supports the notion that LC is an initiation site of HPt pathology. This may suggest that development of clinical assessment techniques and radiological investigations reflecting early LC alterations may help in identifying subjects with early stages of neurodegeneration. Furthermore, we studied a large cohort of cognitively unimpaired subjects with age at death ≥50 years and we applied the National Institute on Aging –Alzheimer’s disease (AD) Association (NIA-AA) guidelines for the assessment of AD related neuropathological changes. Interestingly, a considerable percentage of the subjects were classified as having an intermediate level of AD pathology. We also showed that the altered proteins;  HPt , Aβ, αS, and TDP43 are frequently seen in the brain of cognitively unimpaired subjects with age at death ≥50 years, the incidence of these proteins increased significantly with age. This finding suggests that neurodegeneration has to be extensive to cause functional disturbance and clinical symptoms. Moreover, we investigated the correlation between AD related pathology in cortical biopsies, the AD / cerebrospinal fluid (CSF) biomarkers and the Mini Mental State examination (MMSE) scores in a cohort of idiopathic Normal Pressure Hydrocephalus (iNPH) patients. We demonstrated that AD/ CSF biomarkers and MMSE scores reflect AD pathology in the cortical biopsies obtained from iNPH patients.  In conclusion, this study shows that the altered proteins associated with neurodegeneration are frequently seen in the brain tissue of cognitively unimpaired aged subjects. This fact should be considered while developing diagnostic biomarkers for identification of subjects at early stages of the disease, in order to introduce therapeutic intervention prior to the occurrence of significant cognitive impairment.
22

Alterações neuroimunoendócrinas em animais sobreviventes à sepse / Neuroimmunoendocrine alterations in sepsis survivor animals

Júnior, Nilton Nascimento dos Santos 30 August 2018 (has links)
Durante a sepse ocorre liberação de mediadores inflamatórios, que contribui para o comprometimento do sistema nervoso central e alterações na secreção dos hormônios hipofisários. Contudo, não está elucidado se essas alterações persistem em animais sobreviventes à sepse. Nesse contexto, o objetivo deste trabalho foi estudar as alterações neuroimunoendócrinas em animais sobreviventes à sepse polimicrobiana experimental. A sepse foi induzida pelo método de ligadura e perfuração cecal (CLP) (uma perfuração com agulha 14G) e os animais foram observados durante cinco ou dez dias. Os animais naive ou sobreviventes foram submetidos ao desafio osmótico intraperitoneal com salina hipertônica (2M), ou desafio imune intravenoso com LPS (1.5 mg/kg), ou ao estresse por imobiliza- ção. Após 30 minutos do desafio osmótico ou 60 minutos para os demais estímulos, os animais foram decapitados para coleta de sangue e do hipotálamo. O sangue foi coletado para dosagem de nitrato, citocinas e hormônios (vasopressina, ocitocina, ACTH e corticosterona); e o hipotálamo para a quantificação dos níveis de citocinas e dos conteúdos de sinaptofisina e beta-amilóide. No presente estudo, nós observamos um aumento periférico dos mediadores inflamatórios: nitrato e IL-1?, e centralmente da citocina IL-6 no hipotálamo de animais sobreviventes à sepse. Além disso, dependendo do estímulo, observou-se uma atenuada (desafio osmótico) ou exacerbada (desafio imune) secreção da vasopressina e/ou ocitocina em animais sobreviventes à sepse. Adicionalmente, também encontramos uma diminuição no conteúdo hipotalâmico de sinaptofisina, e nenhum sinal de acúmulo de beta-amilóide. Concluímos que as alterações na secreção de vasopressina e ocitocina observadas podem estar associadas à neuroinflamação sustentada e disfunção sináptica com evidências de processo neurodegenerativo. Este modelo de sepse pode fornecer informações importantes para a compreensão das alterações fisiopatológicas à longo prazo. / Inflammatory mediators released during sepsis contribute to central nervous system impairment and alterations in the secretion of pituitary hormones. However, it is unclear whether these changes persist in sepsis survivor animals. In this context, the objective of this work was to study the neuroimunoendocrine alterations in sepsis survivor animals. Sepsis was induced by the cecal ligation and perforation (CLP) method and the animals (perforated once with a 14G needle) were observed for five or ten days. Naive or sepsis survivors were submitted to intraperitoneal osmotic challenge with hypertonic saline (2M), or intravenous immune challenge with LPS (1.5 mg/kg), or immobilization stress. After 30 minutes of the osmotic challenge or 60 minutes for the other stimuli, the animals were decapitated for collection of blood and the hypothalamus. Blood was collected for the determination of nitrate, cytokines and hormones (vasopressin, oxytocin, ACTH and corticosterone); and the hypothalamus for quantification of cytokine levels, and synaptophysin and beta-amyloid contents. In the present study, we observed a peripheral increase of inflammatory mediators: nitrate and IL-1?, and centrally of the IL-6 cytokine in the hypothalamus of sepsis survivor animals. In addition, depending on the stimulus, an attenuated (osmotic challenge) or exacerbated (immune challenge) secretion of vasopressin and/or oxytocin was observed in sepsis survivor animals. In addition, we also found a decrease in the hypothalamic content of synaptophysin, and no signal of beta amyloide accumulation. We conclude that alterations in vasopressin and oxytocin secretion may be associated with sustained neuroinflammation and synaptic dysfunction with evidence of neurodegenerative process. This model of sepsis may provide important informations for understanding long-term pathophysiological alterations.
23

Planejamento, ensaio e otimização in silico de novos protótipos inibidores da enzima acetilcolinesterase / Design, assay and in silico optimization of new prototypes inhibitors of acetylcholinesterase

Almeida, Jonathan Resende de 26 January 2015 (has links)
A acetilcolinesterase (AChE) é uma enzima essencial que encerra a transmissão colinérgica através de uma rápida hidrólise do neurotransmissor, acetilcolina (ACh). Uma ampla série de evidências mostraram que os inibidores da AChE podem interferir com a progressão da doença de Alzheimer (DA). O desenvolvimento bem sucedido de compostos inibidores da AChE foi baseado na teoria de que o declínio nas funções cognitivas e mentais associadas a DA está relacionado com a perda da neurotransmissão cortical colinérgica, sendo assim, esses compostos podem ser usados para tratar as deficiências colinérgicas. Uma coleção de moléculas orgânicas foi escaneada para ser avaliada a capacidade dessas moléculas em inibir a atividade enzimática da AChE com o objetivo de se encontrar compostos líderes para posteriores otimizações, conduzindo a fármacos com aumento da eficácia e/ou menores efeitos adversos. As estratégias aplicadas incluem o screening ou triagem virtual baseado na estrutura e também no ligante, modelagem farmacofórica, docking molecular e buscas por similaridade (forma e eletrostática). Os estudos foram também concentrados na descoberta de novas classes de inibidores da AChE, tendo como molécula de referência o fármaco donepezil, o qual inaugurou uma nova classe de inibidores da AChE com a ação mais longa e mais seletiva com efeitos adversos manejáveis. Do total de compostos triados, 50 foram selecionados com adequadas propriedades físico-químicas e ADME/Tox. Em geral, esses compostos possuem substancial interação com o sítio periférico aniônico (PAS) da AChE e a maioria deles faz interações adicionais com o sítio catalítico (CAS) e com outros resíduos de aminoácidos importantes ao longo da enzima. Destes 50 compostos, oito foram comercialmente adquiridos e os ensaios enzimáticos revelaram que estes compostos exibem uma alta afinidade pela AChE. Os resultados apontam, ainda, que o composto entitulado ZINC30019441 exibiu a mais potente atividade inibitória para a AChE, com 1,8 micromolar de concentração, e os demais ficaram ainda situados em baixo micromolar, de 2 a 3 micromolar de concentração. Estes resultados, além das modificações químicas ora propostas in silico para estes inibidores protótipos, apontam para o desenvolvimento de uma nova e promissora série de potentes anticolinesterásicos, contendo propriedades de fármacos, as quais são ainda apropriadas para atuarem no Sistema Nervoso Central e interagirem com o peptídeo beta-amiloide, com vistas ao tratamento quimioterápico da doença de Alzheimer. A perspectiva imediata inclui os ensaios de anti-agregação do peptídeo com os oito inibidores já testados com a Acetilcolinesterase. / Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by rapid hydrolysis of the neurotransmitter acetylcholine (ACh). A wide range of evidence shows that AChE inhibitors may interfere with the progression of Alzheimer\'s disease (AD). The successful development of AChE inhibitor compounds was based on the theory that the decline in cognitive and mental functions associated with AD is related to the loss of cortical cholinergic neurotransmission, thus, these compounds can be used for treating cholinergic deficiencies. A collection of organic molecules has been scanned to evaluate the ability of these molecules to inhibit the enzymatic activity of AChE in order to find lead compounds for further optimization, leading to drugs with increased efficacy and/or fewer adverse effects. The strategies applied include structure-based virtual screening and also in ligand-based virtual screening, pharmacophoric modeling, molecular docking and similarity searches (shape and electrostatic). Studies have also focused on the discovery of new classes of AChE inhibitors, having as a reference molecule the drug donepezil, which has opened a new class of AChE inhibitors with longer and more selective action with manageable side effects. 50 of the compounds screened, were selected with appropriate physical and chemical properties and ADME/Tox. In general, these compounds possess substantial interaction with the peripheral anionic site (PAS) of AChE and most of them make further interact with the catalytic site (CAS) and other key amino acid residues throughout the enzyme. Out of these 50 compounds, eight were commercially purchased and the enzyme assays have shown that these compounds exhibit a high affinity for AChE. The results show also that the compound titled ZINC30019441 exhibited the most potent inhibitory activity for AChE, with 1.8 micromolar concentration, and the rest were still located in low micromolar, 2-3 micromolar concentration. These results as well as chemical modifications herein proposed for these prototypes, indicate the development of a new and promising series of potent anticholinesterase containing drug properties, which are still suitable to act on the central nervous system and interact with the ?-amyloid peptide, for chemotherapy treatment of Alzheimer\'s disease. The immediate prospect includes the peptide anti-aggregation assays with the eight inhibitors already tested against acetylcholinesterase
24

Planejamento, ensaio e otimização in silico de novos protótipos inibidores da enzima acetilcolinesterase / Design, assay and in silico optimization of new prototypes inhibitors of acetylcholinesterase

Jonathan Resende de Almeida 26 January 2015 (has links)
A acetilcolinesterase (AChE) é uma enzima essencial que encerra a transmissão colinérgica através de uma rápida hidrólise do neurotransmissor, acetilcolina (ACh). Uma ampla série de evidências mostraram que os inibidores da AChE podem interferir com a progressão da doença de Alzheimer (DA). O desenvolvimento bem sucedido de compostos inibidores da AChE foi baseado na teoria de que o declínio nas funções cognitivas e mentais associadas a DA está relacionado com a perda da neurotransmissão cortical colinérgica, sendo assim, esses compostos podem ser usados para tratar as deficiências colinérgicas. Uma coleção de moléculas orgânicas foi escaneada para ser avaliada a capacidade dessas moléculas em inibir a atividade enzimática da AChE com o objetivo de se encontrar compostos líderes para posteriores otimizações, conduzindo a fármacos com aumento da eficácia e/ou menores efeitos adversos. As estratégias aplicadas incluem o screening ou triagem virtual baseado na estrutura e também no ligante, modelagem farmacofórica, docking molecular e buscas por similaridade (forma e eletrostática). Os estudos foram também concentrados na descoberta de novas classes de inibidores da AChE, tendo como molécula de referência o fármaco donepezil, o qual inaugurou uma nova classe de inibidores da AChE com a ação mais longa e mais seletiva com efeitos adversos manejáveis. Do total de compostos triados, 50 foram selecionados com adequadas propriedades físico-químicas e ADME/Tox. Em geral, esses compostos possuem substancial interação com o sítio periférico aniônico (PAS) da AChE e a maioria deles faz interações adicionais com o sítio catalítico (CAS) e com outros resíduos de aminoácidos importantes ao longo da enzima. Destes 50 compostos, oito foram comercialmente adquiridos e os ensaios enzimáticos revelaram que estes compostos exibem uma alta afinidade pela AChE. Os resultados apontam, ainda, que o composto entitulado ZINC30019441 exibiu a mais potente atividade inibitória para a AChE, com 1,8 micromolar de concentração, e os demais ficaram ainda situados em baixo micromolar, de 2 a 3 micromolar de concentração. Estes resultados, além das modificações químicas ora propostas in silico para estes inibidores protótipos, apontam para o desenvolvimento de uma nova e promissora série de potentes anticolinesterásicos, contendo propriedades de fármacos, as quais são ainda apropriadas para atuarem no Sistema Nervoso Central e interagirem com o peptídeo beta-amiloide, com vistas ao tratamento quimioterápico da doença de Alzheimer. A perspectiva imediata inclui os ensaios de anti-agregação do peptídeo com os oito inibidores já testados com a Acetilcolinesterase. / Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by rapid hydrolysis of the neurotransmitter acetylcholine (ACh). A wide range of evidence shows that AChE inhibitors may interfere with the progression of Alzheimer\'s disease (AD). The successful development of AChE inhibitor compounds was based on the theory that the decline in cognitive and mental functions associated with AD is related to the loss of cortical cholinergic neurotransmission, thus, these compounds can be used for treating cholinergic deficiencies. A collection of organic molecules has been scanned to evaluate the ability of these molecules to inhibit the enzymatic activity of AChE in order to find lead compounds for further optimization, leading to drugs with increased efficacy and/or fewer adverse effects. The strategies applied include structure-based virtual screening and also in ligand-based virtual screening, pharmacophoric modeling, molecular docking and similarity searches (shape and electrostatic). Studies have also focused on the discovery of new classes of AChE inhibitors, having as a reference molecule the drug donepezil, which has opened a new class of AChE inhibitors with longer and more selective action with manageable side effects. 50 of the compounds screened, were selected with appropriate physical and chemical properties and ADME/Tox. In general, these compounds possess substantial interaction with the peripheral anionic site (PAS) of AChE and most of them make further interact with the catalytic site (CAS) and other key amino acid residues throughout the enzyme. Out of these 50 compounds, eight were commercially purchased and the enzyme assays have shown that these compounds exhibit a high affinity for AChE. The results show also that the compound titled ZINC30019441 exhibited the most potent inhibitory activity for AChE, with 1.8 micromolar concentration, and the rest were still located in low micromolar, 2-3 micromolar concentration. These results as well as chemical modifications herein proposed for these prototypes, indicate the development of a new and promising series of potent anticholinesterase containing drug properties, which are still suitable to act on the central nervous system and interact with the ?-amyloid peptide, for chemotherapy treatment of Alzheimer\'s disease. The immediate prospect includes the peptide anti-aggregation assays with the eight inhibitors already tested against acetylcholinesterase
25

Passive Immunisierung mit einem N-trunkierten Abetaspezifischen Antikörper - Therapeutisches Potential von NT4X in einem familiären Alzheimer-Mausmodell / Passive immunisation with a N-truncated abeta specific antibody - therapeutic potential of NT4X in a familial Alzheimer mouse model

Ueberück, Maximilian 26 March 2019 (has links)
No description available.
26

Gamma-AApeptides as a New Class of Peptidomimetics: Synthesis, Structures, and Functions

Wu, Haifan 15 February 2015 (has links)
Peptidomimetics are synthetic oligomers that resemble the activities of peptides. Their advantages over peptides include high stability towards proteolysis and enormous chemical diversity. Over the past two decades, there have been extensive efforts to develop peptide mimics, such as beta-peptides, peptoids, D-peptides, etc. The research on peptidomimetics have led to many important applications in both medicinal and material science. In order to explore new functions, the discovery of peptidomimetics with novel frameworks is essential. We reported the synthesis and evaluation of a new class of peptidomimetics, termed as gamma-AApeptides. Previous studies of gamma-AApeptides have revealed that gamma-AApeptides are highly resistant to proteolysis, and are highly amendable to chemical diversification. However, new biological activities and folding properties of gamma-AApeptides still need to be explored. In order to expand the potential of gamma-AApeptides in chemical biology and medicinal chemistry, I have been focusing on the development of new methods to synthesize linear and cyclic gamma-AApeptides, development of one-bead-one-compound (OBOC) gamma-AApeptide libraries for the discovery of inhibitors against beta-amyloid aggregation, exploring new helical foldamers for the rational design of protein-protein interaction (PPI) inhibitors, and studying cyclic gamma-AApeptides for antimicrobial development.
27

Metallopeptides From Design to Catalysis: Structure, Oxidative Activities, And Inhibition Studies Of Designed And Naturally Occurring Metallopeptides

Hashim, Alaa Hassan 19 November 2014 (has links)
Structural and mechanistic complexities of copper-dioxygen systems have attracted much attention in the field of bioinorganic chemistry, both in model systems and trapped protein intermediates. The research presented herein is focused on model and naturally occurring metallopeptide systems, from its design to catalysis. Copper is used as the coordinating metal ion, with cobalt and zinc as probes for metal binding. The bioinorganic chemistry of copper proteins and its coordination and spectroscopic properties are briefly discussed in chapter 1. The next two chapters are centered on the de novo design of a minimalistic metallopeptide system with an amino acid sequence of RHHPPHHE. Structural characterization of the peptide by means of CD and NMR spectroscopy techniques are presented in chapter 2, suggesting a characteristic beta-turn structure in its apo and di-metal bound form. The designed metallopeptide exhibits catecholase activity, which is presented in chapter 3. The data suggest the presence of two mononuclear copper active sites, exhibiting specificity towards the oxidation of catecholamine substrates. Similarly, the catecholase activity has been previously observed in copper complexes of Alzheimer's disease related peptide beta-amyloid, exhibiting metal-centered redox chemistry. The metallo-(beta-amyloid); complexes are the hallmark Alzheimer's disease and have been attributed to the generation of reactive oxygen species causing oxidative stress. Thus, inhibition of the observed oxidative activities was investigated. Probing the role of phosphate moieties in various compounds as potential inhibitors against the induced oxidative stress is presented in chapter 4. The phosphate analogs of the studied compounds exhibit more pronounced potency, where mutation of the beta amyloid peptide at Arg-5 and Lys-16 give insight into the interactions of the side chains of Arg and Lys with the phosphate moiety. 31P NMR relaxation studies further support the binding/interaction of phosphate with the Cu(II)-(beta-amyloid); complexes. The correlation of phosphate moiety binding/activity will allow for the design of more potent inhibitors toward the Cu(II)-(beta-amyloid); induced oxidative stress.
28

The potential involvement of semicarbazide-sensitive amine oxidase-mediated reactions and aldehyde stress in the aggregation, cytotoxicity and clearance of beta-amyloid related to Alzheimer's disease

Chen, Kun 13 January 2010
Beta-amyloid (Aâ) remains to be the focus of research interest of the pathogenesis of Alzheimers disease (AD). Aâ is subject to oligomerization and its polymers are cytotoxic. Advanced aggregation leads to formation of senile plaques. Depositions of Aâ surrounding the cerebral vasculature, i.e. cerebral amyloid angiopathy (CAA), occur in most AD patients. The occurrence of Aâ aggregation in AD brains is not due to over-expression of amyloid precursor protein in most cases of AD. Factors influencing Aâ polymerization are yet to be established.<p> Aldehydes are highly reactive. They can cause protein crosslinkage. It is interesting to study whether endogenous aldehydes may be involved in Aâ polymerization process. In order to investigate the potential interaction of endogenous aldehydes with Aâ and their effects on its aggregation, various techniques including thioflavin T fluometry, dynamic light scattering, circular dichroism and atomic force microscopy were employed to assess Aâ aggregation at different stages. Formaldehyde, methylglyoxal, malondialdehyde and 4-hydroxyl-nonenal were found to enhance Aâ â-sheets formation, oligomerization and fibrillogenesis in vitro. The sizes of the oligomers are increased after interaction with the aldehydes. Lysine residues of Aâ were identified to be the primary site of interaction with aldehydes by forming Schiff bases, which may subsequently lead to intra- and inter-molecular crosslinkage. Aldehydes can also crosslink Aâ with other proteins such as apolipoprotein E and á2-macroglobulin (á2M), to form large complexes. Results suggest that aldehydes substantially increase the rate of Aâ oligomerization at each stage of fibrillogenesis.<p> The native and formaldehyde-modified Aâ oligomers were isolated by size exclusion chromatography and their cytotoxic effects towards SH-SY5Y neuroblastoma cells were assessed using MTT, LDH and caspase-3 activity assays. The aldehyde-modified oligomers are slightly but significantly more cytotoxic compared to the native oligomers. Since aldehydes significantly increase the production of Aâ oligomers, an increase in aldehydes would enhance the total cytotoxicity, suggesting that aldehydes may potentially exacerbate neurovascular damage and neurodegeneration caused by Aâ.<p> Low-density lipoprotein receptor related protein-1 (LRP-1) plays a crucial role in Aâ clearance via the cerebral vasculature. Semicarbazide-sensitive amine oxidase (SSAO) and LRP-1 are both richly expressed on the vascular smooth muscle cells (VSMCs). We demonstrated that SSAO-mediated deamination affects LRP-1 function using isolated VSMCs. Formaldehyde at low concentrations decreases LRP-1-mediated uptake of á2M, a substrate of LRP-1 and a carrier for Aâ. Methylamine, an SSAO substrate that is converted to formaldehyde, also inactivates LRP-1 function, but not in the presence of an SSAO inhibitor. Increased SSAO-mediated deamination can potentially impair Aâ clearance via LRP-1.<p> In conclusion, aldehydes derived from oxidative stress and SSAO-mediated deamination induce Aâ aggregation, enhance Aâ cytotoxicity and impair Aâ clearance. The exclusive localization of SSAO on the cerebral vasculature may be responsible for the perivascular deposition of Aâ, i.e. CAA, which is associated both with vascular dementia and with AD. Vascular surface SSAO may be a novel pharmacological target for the treatment of AD.
29

Lack of neuroprotective effects by platelet-derived growth factor against beta-amyloid induced toxicity uncovers a novel hypothesis of Alzheimer's disease pathology

Liu, Hui 04 May 2012 (has links)
Aβ oligomer-induced neurotoxicity has become an important area of therapeutic development in treating Alzheimer’s disease. Platelet-derived growth factor (PDGF) has been shown to be able to protect neurons against several neuronal insults such as ischemia and HIV1 toxin induced cytotoxicity. These neuroprotective effects correlate well with our previous results that demonstrate the neuroprotective effects of PDGF-BB, one of the PDGF receptor ligand subtypes, against NR2B containing NMDA receptor induced excitotoxicity, a possible underlying cause of Aβ oligomer induced synaptic dysfunction and neuronal death. This project examines the neuroprotective effect of PDGF-BB against Aβ1-42 oligomer induced cytotoxicity in both SH-SY5Y cells and primary hippocampal neurons. Cell viability was monitored by MTT assay and the affected signaling pathways were examined using pharmacological methods and Western blotting. The results demonstrated that Aβ1-42 oligomer elicited a dose-dependent toxicity with a sign of saturation at higher dosages, PDGF-BB failed to protect neurons against Aβ1-42 oligomer induced cytotoxicity. In contrast, Aβ1-42 oligomers strongly inhibit PDGF-BB induced mitogenesis in both SH-SY5Y cells and primary neurons. Further investigation using Western blotting to measure PDGF receptor expression and phosphorylation in SH-SY5Y cells showed that Aβ1-42 oligomer can inhibit PDGF-BB induced phosphorylation of PDGF β-receptor on Tyr1021, a site that is crucial for PLCγ mediated mitogenesis. These findings not only explained the poor neuroprotective effect elicited by PDGF-BB against Aβ1-42 oligomers, but also led to a novel hypothesis that Aβ1-42 oligomer may interfere with neurotrophic factor induced neuronal survival, either selectively or perhaps globally. Further exploration on this hypothesis will be able to shed light on this potentially novel mechanism of pathogenesis in Alzheimer’s disease.
30

The potential involvement of semicarbazide-sensitive amine oxidase-mediated reactions and aldehyde stress in the aggregation, cytotoxicity and clearance of beta-amyloid related to Alzheimer's disease

Chen, Kun 13 January 2010 (has links)
Beta-amyloid (Aâ) remains to be the focus of research interest of the pathogenesis of Alzheimers disease (AD). Aâ is subject to oligomerization and its polymers are cytotoxic. Advanced aggregation leads to formation of senile plaques. Depositions of Aâ surrounding the cerebral vasculature, i.e. cerebral amyloid angiopathy (CAA), occur in most AD patients. The occurrence of Aâ aggregation in AD brains is not due to over-expression of amyloid precursor protein in most cases of AD. Factors influencing Aâ polymerization are yet to be established.<p> Aldehydes are highly reactive. They can cause protein crosslinkage. It is interesting to study whether endogenous aldehydes may be involved in Aâ polymerization process. In order to investigate the potential interaction of endogenous aldehydes with Aâ and their effects on its aggregation, various techniques including thioflavin T fluometry, dynamic light scattering, circular dichroism and atomic force microscopy were employed to assess Aâ aggregation at different stages. Formaldehyde, methylglyoxal, malondialdehyde and 4-hydroxyl-nonenal were found to enhance Aâ â-sheets formation, oligomerization and fibrillogenesis in vitro. The sizes of the oligomers are increased after interaction with the aldehydes. Lysine residues of Aâ were identified to be the primary site of interaction with aldehydes by forming Schiff bases, which may subsequently lead to intra- and inter-molecular crosslinkage. Aldehydes can also crosslink Aâ with other proteins such as apolipoprotein E and á2-macroglobulin (á2M), to form large complexes. Results suggest that aldehydes substantially increase the rate of Aâ oligomerization at each stage of fibrillogenesis.<p> The native and formaldehyde-modified Aâ oligomers were isolated by size exclusion chromatography and their cytotoxic effects towards SH-SY5Y neuroblastoma cells were assessed using MTT, LDH and caspase-3 activity assays. The aldehyde-modified oligomers are slightly but significantly more cytotoxic compared to the native oligomers. Since aldehydes significantly increase the production of Aâ oligomers, an increase in aldehydes would enhance the total cytotoxicity, suggesting that aldehydes may potentially exacerbate neurovascular damage and neurodegeneration caused by Aâ.<p> Low-density lipoprotein receptor related protein-1 (LRP-1) plays a crucial role in Aâ clearance via the cerebral vasculature. Semicarbazide-sensitive amine oxidase (SSAO) and LRP-1 are both richly expressed on the vascular smooth muscle cells (VSMCs). We demonstrated that SSAO-mediated deamination affects LRP-1 function using isolated VSMCs. Formaldehyde at low concentrations decreases LRP-1-mediated uptake of á2M, a substrate of LRP-1 and a carrier for Aâ. Methylamine, an SSAO substrate that is converted to formaldehyde, also inactivates LRP-1 function, but not in the presence of an SSAO inhibitor. Increased SSAO-mediated deamination can potentially impair Aâ clearance via LRP-1.<p> In conclusion, aldehydes derived from oxidative stress and SSAO-mediated deamination induce Aâ aggregation, enhance Aâ cytotoxicity and impair Aâ clearance. The exclusive localization of SSAO on the cerebral vasculature may be responsible for the perivascular deposition of Aâ, i.e. CAA, which is associated both with vascular dementia and with AD. Vascular surface SSAO may be a novel pharmacological target for the treatment of AD.

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