Avaliação do impacto do peptídeo Aβ42 em diferentes conformações oligoméricas sobre comportamento, memória e autofagia em peixe zebra

Abstract

The incidence of Alzheimer's disease (AD) has increased considerably and the established therapeutic practices remain palliative. AD is characterized by the presence of beta-amyloid (Aβ) plaques and neurofibrillary tangles of Tau protein. Aβ is a peptide of varying sizes between 39 and 43 amino acids, of which Aβ42 is the most pathogenic and abundant in plaques and has the greatest aggregation potential. The soluble oligomeric forms of Aβ have been shown to have the potential to interact with membrane receptors and metabolic targets leading to synaptic failures, cognitive deficits and neuronal death while fibrillar forms tend to aggregate. Autophagy was recently revised and is currently suggested as an underlying process associated with AD. We assessed the impact of cerebroventricular injection (cvi) of human Aβ42 peptide solutions in different oligomeric conformations - monomeric, oligomeric and fibrillar - on the behavioral parameters of the adult zebrafish associated with locomotion, anxiety and long-term memory (LTM). Aβ42 Cvi caused a significant decrease in the exploration of a new tank measured by the reduced distance traveled and the average speed only in the injected fibril group, taken together these results suggest a treatment tendency to reduce exploration. There was a statistically significant treatment-induced reduction in the number of entries in the top zone in the monomer, oligomer and fibril groups in relation to the controls and in the time spent in the top zone in the monomer group in relation to the control group. These parameters suggest a slight anxiogenic effect of Aβ42.LTM for the inhibitory avoidance test was significantly impaired in groups treated with soluble Aβ42 monomeric or oligomeric forms, whose memory formation was impaired. These results corroborate the evidence that soluble forms may be more harmful to cognition and LTM. Brain levels of LC3, a central protein in the autophagy pathway widely used as a marker for autophagosomes, were also estimated using western blotting. The cerebral immunocontent LC3 was increased in animals that received oligomers and fibrils, suggesting that oligomers and Aβ42 fibrils increase the autophagic structures in the brain. The increase in autophagic structures observed does not necessarily indicate an increase in the physiological autophagic flow, it is possible that it is a reflection of a pathological interruption in the autophagic flow that leads to the accumulation of not degraded autophagic structures and neuronal death. In summary, we demonstrated that the cβ of Aβ42 in different soluble oligomeric conformations reflects a subtle tendency to reduce locomotion, increase anxiogenic behavior, reduce LTM and increase autophagic structures in the zebra fish brain.