1. Alzheimers disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling.
- Author
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Zoltowska, Katarzyna, Das, Utpal, Lismont, Sam, Enzlein, Thomas, Maesako, Masato, Houser, Mei, Franco, Maria, Özcan, Burcu, Gomes Moreira, Diana, Karachentsev, Dmitry, Becker, Ann, Hopf, Carsten, Vilar, Marçal, Berezovska, Oksana, Mobley, William, and Chávez-Gutiérrez, Lucía
- Subjects
Alzheimers disease ,amyloid beta ,amyloid toxicity ,biochemistry ,chemical biology ,gamma-secretase ,gamma-secretase inhibition ,human ,mouse ,neuroscience ,presenilin ,rat ,Amyloid Precursor Protein Secretases ,Amyloid beta-Peptides ,Humans ,Alzheimer Disease ,Signal Transduction ,Animals ,Neurons ,Mice ,Feedback ,Physiological ,Peptide Fragments ,Cell Line - Abstract
Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimers disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aβ42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We conducted kinetic analyses of γ-secretase activity in cell-free systems in the presence of Aβ, as well as cell-based and ex vivo assays in neuronal cell lines, neurons, and brain synaptosomes to assess the impact of Aβ on γ-secretases. We show that human Aβ42 peptides, but neither murine Aβ42 nor human Aβ17-42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75, and pan-cadherin. Moreover, Aβ42 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 Aβ42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aβ toxicity in the context of γ-secretase-dependent homeostatic signaling.
- Published
- 2024