Fosgonimeton attenuates amyloid-beta toxicity in preclinical models of Alzheimer's disease

Sherif M Reda; Sharay E Setti; Andrée-Anne Berthiaume; Wei Wu; Robert W Taylor; Jewel L Johnston; Liana R Stein; Hans J Moebius; Kevin J Church

doi:10.1016/j.neurot.2024.e00350

Fosgonimeton attenuates amyloid-beta toxicity in preclinical models of Alzheimer's disease

Neurotherapeutics. 2024 Apr 9;21(4):e00350. doi: 10.1016/j.neurot.2024.e00350. Online ahead of print.

Authors

Sherif M Reda¹, Sharay E Setti¹, Andrée-Anne Berthiaume¹, Wei Wu¹, Robert W Taylor¹, Jewel L Johnston¹, Liana R Stein¹, Hans J Moebius¹, Kevin J Church²

Affiliations

¹ Athira Pharma, Inc., 18706 North Creek Parkway, Suite 104, Bothell, WA, 98011, USA.
² Athira Pharma, Inc., 18706 North Creek Parkway, Suite 104, Bothell, WA, 98011, USA. Electronic address: kevin.church@athira.com.

PMID: 38599894
DOI: 10.1016/j.neurot.2024.e00350

Abstract

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 (Aβ_1-42), 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 Aβ_25-35 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).

Keywords: Alzheimer's disease; Amyloid beta; Fosgonimeton; Hepatocyte growth factor (HGF); Neuroprotection; Neurotrophic factor.

Associated data

ClinicalTrials.gov/NCT04488419
ClinicalTrials.gov/NCT04886063