Alzheimer's disease linked Aβ42 exerts product feedback inhibition on γsecretase impairing downstream cell signaling

Zoltowska, K. M.; Utpal, D.; Lismont, S.; Enzlein, T.; Maesako, M.; Houser, M. C.; Gomes Moreira, D.; Franco, M. L.; Karachentsev, D.; Becker, A.; Hopf, C.; Vilar, M.; Berezovska, O.; Mobley, W.; Chavez-Gutierrez, L.

doi:10.1101/2023.08.02.551596

bioRxiv · 10.1101/2023.08.02.551596

Alzheimer's disease linked Aβ42 exerts product feedback inhibition on γsecretase impairing downstream cell signaling

Zoltowska, K. M.·Utpal, D.·Lismont, S.·Enzlein, T.·Maesako, M.·Houser, M. C.·Gomes Moreira, D.·Franco, M. L.·Karachentsev, D.·Becker, A.·Hopf, C.·Vilar, M.·Berezovska, O.·Mobley, W.·Chavez-Gutierrez, L.

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Abstract

Amyloid {beta} (A{beta}) 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 A{beta}42 toxicity that arises from its proven affinity for {gamma}-secretases. We hypothesized that the reported increases in A{beta}42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on {gamma}-secretases, and thereby impair downstream signaling events. We show that human A{beta}42 peptides, but neither murine A{beta}42 nor human A{beta}17-42 (p3), inhibit {gamma}-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75 and pan-cadherin. Moreover, A{beta}42 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 A{beta}42 contribute to cellular toxicity via the {gamma}-secretase inhibition, and provide a novel conceptual framework to address A{beta} toxicity in the context of {gamma}-secretase-dependent homeostatic signaling.

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Zoltowska, K. M., Utpal, D., Lismont, S., Enzlein, T., Maesako, M., Houser, M. C., Gomes Moreira, D., Franco, M. L., Karachentsev, D., Becker, A., Hopf, C., Vilar, M., Berezovska, O., Mobley, W., Chavez-Gutierrez, L.. 2023-08-02. Alzheimer's disease linked Aβ42 exerts product feedback inhibition on γsecretase impairing downstream cell signaling. https://doi.org/10.1101/2023.08.02.551596

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