Amyloid Ξ² (AΞ²) peptides accumulating in the brain are proposed to trigger Alzheimerβs disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for AΞ²42 toxicity that arises from its proven affinity for Ξ³-secretases. We hypothesized that the reported increases in AΞ²42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on Ξ³-secretases, and thereby impair β¦