Efeito da injeção da proteína b-amiloide 1-42 em diferentes formas no ventrículo encefálico : um modelo de aspectos celulares da doença de Alzheimer em zebrafish

Abstract

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 amyloidβ peptide (Aβ) that accumulates in senile plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein. The amyloid cascade initially proposed to explain the effects of Aβ pointed to the plaques as the most toxic form of the Aβ 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 Aβ1-42 prepared to have different aggregation potentials: monomeric, oligomeric and plaqueforming. At 5 days post-fertilization (dpf), quantification of Aβ1-42 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 Aβ1- oligomeric forms may induce significant neurotoxic effects and result in cognitive deficits specially at disease’s early stages.