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Doctoral Thesis
DOI
10.11606/T.5.2007.tde-03052007-093430
Document
Author
Full name
Isis Amaral Zainaghi
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2007
Supervisor
Committee
Gattaz, Wagner Farid (President)
Bottino, Cassio Machado de Campos
Mazzacoratti, Maria da Graça Naffah
Nitrini, Ricardo
Santos, Márcia Regina Machado dos
Title in Portuguese
Fosfolipase A2, fluidez de membrana e proteína precursora do amilóide em plaquetas na doença de Alzheimer e comprometimento cognitivo leve
Keywords in Portuguese
Doença de Alzheimer
Fluidez de membrana
Fosfolipases A
Idoso
Marcadores biológicos
Plaquetas
Proteína do amilóide
Transtornos cognitivos
Abstract in Portuguese
A Doença de Alzheimer (DA) é uma desordem neurodegenerativa progressiva que causa comprometimento cognitivo em idosos. O diagnóstico clínico da DA é complexo. Existe uma grande necessidade de técnicas capazes de detectar a doença nos estágios iniciais, tanto para auxiliar o diagnóstico quanto para monitorar a efetividade dos tratamentos disponíveis. As alterações bioquímicas da DA são resultado de processos celulares como o metabolismo da proteína precursora do amilóide (APP), fosforilação da tau, stress oxidativo, inflamação e desregulação lipídica. Até o momento não existem marcadores bioquímicos para auxiliar o diagnóstico da DA. Este trabalho avaliou três possíveis candidatos a marcadores bioquímicos para a DA. Foram investigados a razão da APP (rAPP) de 130/110 kDa, fluidez de membrana e atividade da fosfolipase A2 em plaquetas de pacientes com DA e Comprometimento Cognitivo Leve (CCL), comparando-se seus resultados com controles idosos saudáveis. A fluidez das membranas das plaquetas foi avaliada por meio da anisotropia com a sonda fluorescente DPH (Difenilhexatrieno); a comparação das razões da APP foi realizada por Western Blotting empregando o anticorpo 22C11 e a da atividade da PLA2 foi determinada por ensaio radioenzimático com substratos e concentrações de cálcio específicas para cada um dos três principais grupos da enzima. A rAPP, as atividades da sPLA2 e iPLA2 estavam significantemente reduzidas na DA quando comparadas com controles, enquanto que a cPLA2 e a fluidez de membrana não apresentaram diferenças entre os grupos. A rAPP e a iPLA2 também apresentaram diferenças significativas entre CCL e DA, além de estarem correlacionadas com os parâmetros cognitivos MEEM e CAMCOG. A rAPP também estava correlacionada com a anistropia do DPH.
Title in English
Phospholipase A2, membrane fluidity and amyloid precursor protein in platelets in Alzheimer's disease and mild cognitive impairment
Keywords in English
Aged
Alzheimer disease
Amyloid beta protein
Biological markers
Cognitive disorders
Membrane fluidity
Phospholipases A
Platelets
Abstract in English
Alzheimer disease (AD) is a progressive neurodegenerative disorder that causes cognitive impairment in the elderly. The clinical diagnosis of AD is complex. Thus, there is a great need for sensitive techniques to detect neurodegeneration in the early stages to asset in the diagnosis and to follow the effectiveness of therapy. The biochemical alterations in the AD brain result from cellular processes such as amyloid precursor protein (APP) metabolism, tau phosphorylation, oxidative stress, inflammation and lipid dysregulation. So far there are no biochemical markers to help the AD diagnosis. The purpose of this study was to evaluate three possible candidates to biochemical marker of AD. The APP 130/110 kDa ratio, membrane fluidity and phospholipase A2 activity in platelets of patients with AD and mild cognitive impairment (MCI) were investigated compared to their results with healthy elderly controls. The membrane fluidity of platelets was assessed by the fluorescence anisotropy of DPH (diphenyl-hexatriene); the levels of APP isoforms were evaluated by Western Blot analysis using 22C11 antibody and the PLA2 activity was measured by radio-enzymatic assay with enzyme specific substrate and calcium concentrations for each one of the three main groups of the enzyme. The APP ratio (APPr), the sPLA2 and iPLA2 activity were markedly decreased in AD in comparing with controls, whereas a cPLA2 and membrane fluidity didn't show any alteration between the groups evaluated. The APPr and iPLA2 also showed significant differences between MCI e AD, and were correlated with cognitive parameters MMSE and CAMCOG. The APPr was also correlated with DPH anisotropy.
 
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IsisAZainaghitese.pdf (2.24 Mbytes)
Publishing Date
2007-05-17
 
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