Fosgonimeton attenuates amyloid-beta toxicity in preclinical models of Alzheimer's disease
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved..
Positive modulation of hepatocyte growth factor (HGF) signaling may represent a promising therapeutic strategy for Alzheimer's disease (AD) based on its multimodal neurotrophic, neuroprotective, and anti-inflammatory effects addressing the complex pathophysiology of neurodegeneration. Fosgonimeton is a small-molecule positive modulator of the HGF system that has demonstrated neurotrophic and pro-cognitive effects in preclinical models of dementia. Herein, we evaluate the neuroprotective potential of fosgonimeton, or its active metabolite, fosgo-AM, in amyloid-beta (Aβ)-driven preclinical models of AD, providing mechanistic insight into its mode of action. In primary rat cortical neurons challenged with Aβ (Aβ1-42), fosgo-AM treatment significantly improved neuronal survival, protected neurite networks, and reduced tau hyperphosphorylation. Interrogation of intracellular events indicated that cortical neurons treated with fosgo-AM exhibited a significant decrease in mitochondrial oxidative stress and cytochrome c release. Following Aβ injury, fosgo-AM significantly enhanced activation of pro-survival effectors ERK and AKT, and reduced activity of GSK3β, one of the main kinases involved in tau hyperphosphorylation. Fosgo-AM also mitigated Aβ-induced deficits in Unc-like kinase 1 (ULK1) and Beclin-1, suggesting a potential effect on autophagy. Treatment with fosgo-AM protected cortical neurons from glutamate excitotoxicity, and such effects were abolished in the presence of an AKT or MEK/ERK inhibitor. In vivo, fosgonimeton administration led to functional improvement in an intracerebroventricular Aβ25-35 rat model of AD, as it significantly rescued cognitive function in the passive avoidance test. Together, our data demonstrate the ability of fosgonimeton to counteract mechanisms of Aβ-induced toxicity. Fosgonimeton is currently in clinical trials for mild-to-moderate AD (NCT04488419; NCT04886063).
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:21 |
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| Enthalten in: |
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics - 21(2024), 4 vom: 09. Apr., Seite e00350 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Reda, Sherif M [VerfasserIn] |
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| Links: |
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| Themen: |
Alzheimer's disease |
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| Anmerkungen: |
Date Revised 28.04.2024 published: Print-Electronic ClinicalTrials.gov: NCT04488419, NCT04886063 Citation Status Publisher |
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| doi: |
10.1016/j.neurot.2024.e00350 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 520 | |a Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Positive modulation of hepatocyte growth factor (HGF) signaling may represent a promising therapeutic strategy for Alzheimer's disease (AD) based on its multimodal neurotrophic, neuroprotective, and anti-inflammatory effects addressing the complex pathophysiology of neurodegeneration. Fosgonimeton is a small-molecule positive modulator of the HGF system that has demonstrated neurotrophic and pro-cognitive effects in preclinical models of dementia. Herein, we evaluate the neuroprotective potential of fosgonimeton, or its active metabolite, fosgo-AM, in amyloid-beta (Aβ)-driven preclinical models of AD, providing mechanistic insight into its mode of action. In primary rat cortical neurons challenged with Aβ (Aβ1-42), fosgo-AM treatment significantly improved neuronal survival, protected neurite networks, and reduced tau hyperphosphorylation. Interrogation of intracellular events indicated that cortical neurons treated with fosgo-AM exhibited a significant decrease in mitochondrial oxidative stress and cytochrome c release. Following Aβ injury, fosgo-AM significantly enhanced activation of pro-survival effectors ERK and AKT, and reduced activity of GSK3β, one of the main kinases involved in tau hyperphosphorylation. Fosgo-AM also mitigated Aβ-induced deficits in Unc-like kinase 1 (ULK1) and Beclin-1, suggesting a potential effect on autophagy. Treatment with fosgo-AM protected cortical neurons from glutamate excitotoxicity, and such effects were abolished in the presence of an AKT or MEK/ERK inhibitor. In vivo, fosgonimeton administration led to functional improvement in an intracerebroventricular Aβ25-35 rat model of AD, as it significantly rescued cognitive function in the passive avoidance test. Together, our data demonstrate the ability of fosgonimeton to counteract mechanisms of Aβ-induced toxicity. Fosgonimeton is currently in clinical trials for mild-to-moderate AD (NCT04488419; NCT04886063) | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Alzheimer's disease | |
| 650 | 4 | |a Amyloid beta | |
| 650 | 4 | |a Fosgonimeton | |
| 650 | 4 | |a Hepatocyte growth factor (HGF) | |
| 650 | 4 | |a Neuroprotection | |
| 650 | 4 | |a Neurotrophic factor | |
| 700 | 1 | |a Setti, Sharay E |e verfasserin |4 aut | |
| 700 | 1 | |a Berthiaume, Andrée-Anne |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Taylor, Robert W |e verfasserin |4 aut | |
| 700 | 1 | |a Johnston, Jewel L |e verfasserin |4 aut | |
| 700 | 1 | |a Stein, Liana R |e verfasserin |4 aut | |
| 700 | 1 | |a Moebius, Hans J |e verfasserin |4 aut | |
| 700 | 1 | |a Church, Kevin J |e verfasserin |4 aut | |
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