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Previous issue date: 2017-03-08 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Aging-related diseases are becoming more common. Alzheimer's disease (AD), the most
prevalent form of dementia, includes as initial symptoms cognitive deficits that are
attributed to the toxic effects of amyloid? peptide (A?) that accumulates in senile plaques
and neurofibrillary tangles composed of hyperphosphorylated tau protein. The amyloid
cascade initially proposed to explain the effects of A? pointed to the plaques as the most
toxic form of the A? molecule responsible for neuronal dysfunction and death. Recently,
several evidences point to the increased toxicity of the soluble forms of the peptide. A better
understanding of the dynamics of amyloid aggregation, clearance and toxic potential of the
soluble versions may foster significant advances in the understanding AD mechanisms and
the identification of potential targets for AD therapies. In this study we used the zebrafish as
a model. 24-hour embryos received intracerebroventricular injection of human A?1-42
prepared to have different aggregation potentials: monomeric, oligomeric and plaqueforming.
At 5 days post-fertilization (dpf), quantification of A?1-42 levels demonstrated a
remnant increase in peptide levels in the animals injected with the solution that favored
plaque formation. After monitoring for embryotoxic and teratogenic effects, 5dpf the
animals were also evaluated in relation to general physiological aspects and their cognitive
ability. Although the injection did not significantly impact animal survival or exploratory
ability, the oligomeric solution induced specific cognitive deficits in relation to the vehicleinjected
control. Together these results support the revised version of the amyloid cascade
in which, although the presence of plaques corresponds to a greater accumulation of A?1-
oligomeric forms may induce significant neurotoxic effects and result in cognitive deficits
specially at disease?s early stages. / Com o envelhecimento da popula??o, doen?as relacionadas com o envelhecimento v?m se
tornando mais comuns. A Doen?a de Alzheimer (DA), a forma prevalente de dem?ncia, inclui
como sintomas iniciais deficit cognitivos que s?o atribu?dos a efeitos t?xicos de pept?deo ?-
amiloide (A?) que se acumula em placas senis e emaranhados neurofibrilares constitu?dos
pela prote?na tau hiperfosforilada. A cascata amiloide inicialmente proposta para explicar os
efeitos do A? apontava para as placas de dep?sito de A?1-42 como a forma t?xica da
mol?cula respons?vel pela disfun??o e morte neuronal. Recentemente diversas evid?ncias
apontam para a toxicidade das vers?es sol?veis do pept?deo antes da agrega??o em placas.
O melhor entendimento da din?mica de agrega??o do amiloide, limpeza e potencial t?xico
das vers?es sol?veis pode permitir significativos avan?os no conhecimento dos mecanismos
da doen?a e a identifica??o de potenciais alvos para terapias da DA. Neste estudo utilizamos
o tele?steo zebrafish como modelo para a caracteriza??o destes processos. Embri?es com
24 horas receberam inje??o intracerebroventricular de A?1-42 humano preparado de forma a
ter diferentes potenciais de agrega??o: monom?rica, oligom?rica e formadora de placas. Ao
atingirem 5 dias p?s-fertiliza??o (dpf), a quantifica??o dos n?veis de A?1-42 demonstrou um
aumento remanescente dos n?veis do pept?deo nos animais injetados com a solu??o que
favorecia a forma??o de placas. Ap?s monitorarmos eventuais efeitos embriot?xicos e
teratog?nicos, ao atingirem 5dpf, os animais foram tamb?m avaliados em rela??o a aspectos
fisiol?gicos gerais e sua capacidade cognitiva. Embora a inje??o n?o tenha impactado
significativamente a sobreviv?ncia dos animais ou a capacidade explorat?ria, a inje??o da
solu??o oligom?rica induziu deficit cognitivos espec?ficos em rela??o ao controle injetado
com ve?culo. Juntos, estes resultados suportam a vers?o revisada da cascata amiloide na
qual, embora a presen?a de placas corresponda a um maior ac?mulo de A?1-42, a presen?a
de vers?es oligom?ricas pode induzir efeitos neurot?xicos significativos e resultar em deficit
cognitivos, especialmente nos est?gios iniciais da doen?a.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/7592 |
| Date | 08 March 2017 |
| Creators | Silva, Natalia Eltz |
| Contributors | Vianna, Monica Ryff Moreira Roca |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Biologia Celular e Molecular, PUCRS, Brasil, Faculdade de Bioci?ncias |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da PUC_RS, instname:Pontifícia Universidade Católica do Rio Grande do Sul, instacron:PUC_RS |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 8198246930096637360, 500, 500, 500, 600, 36528317262667714, -1634559385931244697, 2075167498588264571 |
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