Xu, Dongwei; (2025) Understanding the role of metformin in Alzheimer's disease. Doctoral thesis (Ph.D), UCL (University College London).

	Text (Thesis) Thesis Final Deposit.pdf - Accepted Version Access restricted to UCL open access staff until 1 November 2026. Download (5MB)
	Text (Supplemental Material) Table.S2 Analysis results and genotypes of all screened lines.xlsx - Supplemental Material Access restricted to UCL open access staff until 1 November 2026. Download (19kB)
	Text (Supplemental Material) Table.S1 All ordered stocks for the genetic screen.xlsx - Supplemental Material Access restricted to UCL open access staff until 1 November 2026. Download (16kB)

Abstract

Alzheimer’s disease, the most common form of dementia, represents a profound global health burden with urgent need for therapies. Metformin, the first-line drug to treat type II diabetes, is being explored as a potential therapy to treat Alzheimer’s disease following promising results from small-scale clinical trials in patients with mild cognitive impairment that suggest a beneficial role of metformin in ameliorating cognitive decline. However, in vitro experiments report metformin may potentially worsen the disease by increasing the generation of Amyloid-β (Aβ), a widely believed driving force of the pathogenesis of Alzheimer’s disease. To better understand metformin’s role in Alzheimer’s disease, a genetic screen was performed in an Aβproducing Drosophila model for metformin-regulated genes that modify Aβ-associated climbing defect. Multiple candidate suppressors and enhancers of Aβ toxicity were identified, and further validations suggested that the upregulation of rngo (rings lost), which encodes an extraproteasomal ubiquitin receptor, was the best suppressor of toxicity. Metformin could stabilise the rngo protein, possibly through a direct association. The human ortholog of rngo, DDI2 (DNA Damage Inducible 1 Homolog 2), plays a key role in maintaining protein homeostasis, which is in line with the results in flies that both metformin and rngo overexpression could enhance resistance against proteasomal stress. Metformin also suppressed the accumulation of poly-ubiquitinated proteins in human iPSC-derived neurons under proteasome inhibition. Collectively, this project identified a novel target and effector of metformin, rngo/DDI2, that may explain metformin’s benefits in ameliorating Aβ toxicity.

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