Alzheimer's disease risk gene Wwox controls amyloid pathology through metabolic reprogramming.
5 affiliations
- 1Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK.
- 2UK Dementia Research Institute at Cardiff University, School of Medicine, Cardiff CF24 4HQ, UK.
- 3School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
- 4School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol BS8 1QU, UK.
- 5Shared Research Facilities, College of Medical Veterinary Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
Abstract
Genome-wide association studies have identified multiple loci that contribute to late-onset Alzheimer's disease risk, yet the functional mechanisms of many candidate genes remain unclear. WW-domain containing oxidoreductase (WWOX) is one such gene associated with disease and downregulated in patient brains, but its role in neurodegeneration is poorly understood. Here, we use Drosophila models to investigate the cell-type-specific and mechanistic roles of Wwox in ageing and amyloid-β₄₂ (Aβ₄₂)-induced pathology. Neuronal and glial knockdown of Wwox reduced lifespan and increased sleep drive, indicating a role in brain homeostasis. In an Aβ₄₂ transgenic model, neuronal Wwox knockdown exacerbated toxicity, shortening lifespan, impairing locomotion, and increasing soluble Aβ₄₂ levels. Transcriptomic and metabolomic analyses revealed that Wwox knockdown in an Aβ₄₂ transgenic model promotes metabolic reprogramming, characterized by elevated lactate dehydrogenase (Ldh) expression and increased lactate levels, driven by activation of the stress-responsive transcription factor Atf4. Genetic reduction of Ldh rescued locomotor deficits, identifying dysregulated pyruvate metabolism as a key mediator of Wwox-dependent neurotoxicity. Conversely, overexpression of Wwox in neurons markedly reduced amyloid burden, improved survival and locomotor function, and reversed Aβ₄₂-induced transcriptional changes. Both Aβ₄₂ and the protective effects of Wwox were associated with altered amino acid metabolism, including changes in the cysteine and L-methionine pathway. Together, these findings identify WWOX as a regulator of neuronal metabolic state, linking genetic risk to amyloid pathology via metabolic reprogramming, and highlight WWOX activation as a potential therapeutic strategy in Alzheimer's disease.
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BibTeX
@article{lucasclarke2026alzheimers,
title = {{Alzheimer's disease risk gene Wwox controls amyloid pathology through metabolic reprogramming.}},
author = {Hannah J Lucas-Clarke and Daniel C Maddison and Leonardo Amadio and Edgar Buhl and Clement Regnault and Owen M Peters and James J L Hodge and Gaynor A Smith},
journal = {Brain communications},
year = {2026},
month = oct,
doi = {10.1093/braincomms/fcag385},
url = {https://europepmc.org/article/MED/42909904},
note = {CC BY},
}
RIS
TY - JOUR
TI - Alzheimer's disease risk gene Wwox controls amyloid pathology through metabolic reprogramming.
AU - Hannah J Lucas-Clarke
AU - Daniel C Maddison
AU - Leonardo Amadio
AU - Edgar Buhl
AU - Clement Regnault
AU - Owen M Peters
AU - James J L Hodge
AU - Gaynor A Smith
PY - 2026
DA - 2026/10/09
JO - Brain communications
DO - 10.1093/braincomms/fcag385
UR - https://europepmc.org/article/MED/42909904
AB - Genome-wide association studies have identified multiple loci that contribute to late-onset Alzheimer's disease risk, yet the functional mechanisms of many candidate genes remain unclear. WW-domain containing oxidoreductase (WWOX) is one such gene associated with disease and downregulated in patient brains, but its role in neurodegeneration is poorly understood. Here, we use Drosophila models to investigate the cell-type-specific and mechanistic roles of Wwox in ageing and amyloid-β₄₂ (Aβ₄₂)-induced pathology. Neuronal and glial knockdown of Wwox reduced lifespan and increased sleep drive, indicating a role in brain homeostasis. In an Aβ₄₂ transgenic model, neuronal Wwox knockdown exacerbated toxicity, shortening lifespan, impairing locomotion, and increasing soluble Aβ₄₂ levels. Transcriptomic and metabolomic analyses revealed that Wwox knockdown in an Aβ₄₂ transgenic model promotes metabolic reprogramming, characterized by elevated lactate dehydrogenase (Ldh) expression and increased lactate levels, driven by activation of the stress-responsive transcription factor Atf4. Genetic reduction of Ldh rescued locomotor deficits, identifying dysregulated pyruvate metabolism as a key mediator of Wwox-dependent neurotoxicity. Conversely, overexpression of Wwox in neurons markedly reduced amyloid burden, improved survival and locomotor function, and reversed Aβ₄₂-induced transcriptional changes. Both Aβ₄₂ and the protective effects of Wwox were associated with altered amino acid metabolism, including changes in the cysteine and L-methionine pathway. Together, these findings identify WWOX as a regulator of neuronal metabolic state, linking genetic risk to amyloid pathology via metabolic reprogramming, and highlight WWOX activation as a potential therapeutic strategy in Alzheimer's disease.
SN - 2632-1297
ER -