Alzheimer's disease linked Aß42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling.

Amyloid ß (Aß) peptides accumulating in the brain are proposed to trigger Alzheimer's disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aß42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aß42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We show that human Aß42 peptides, but neither murine Aß42 nor human Aß17-42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75 and pan-cadherin. Moreover, Aß42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aß42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aß toxicity in the context of γ-secretase-dependent homeostatic signaling.

Levels and effects of antidepressant drugs to aquatic organisms.

The use of antidepressants has been increasing globally, resulting in their presence in the aquatic environment, mainly by municipal wastewaters. This fact has aroused concern in the scientific community since these biologically active compounds can affect non-target organisms that have physiological systems regulated by these pharmaceuticals. However, the current knowledge on the toxicological effects of antidepressants on aquatic ecosystems is limited. Considering the increasing consumption pattern, quantification studies and toxicity studies, the present work aimed to review the available literature, published in the last seven years, addressing levels of antidepressants and their metabolites in rivers, surface waters, tap water, and wastewater treatment plants, as well, the effects reported in fish and invertebrates. Overall, the available laboratory studies showed that antidepressants can act at different levels of biological organisation, with detrimental effects at the individual level (e.g., survival, growth, and morphology, behaviour, and reproduction). However, the effects of prolonged exposures to environmentally relevant concentrations of these substances, a more realistic scenario, are unknown. Based on short-term studies, the long-term effects of pharmaceuticals at environmentally relevant concentrations (alone and in the presence of other environmental contaminants) should be studied.