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Lithium suppresses Aß pathology by inhibiting translation in an adult Drosophila model of Alzheimer's disease

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posted on 2023-06-09, 08:32 authored by Oyinkan Adesakin, Jorge Castillo-Quan, Charalampos Rallis, Luke Tain, Ivana Bjedov, Iain Rogers, Li Li, Pedro Martinez, Mobina Khericha, Melissa Cabencinha, Jurg Bahler, Linda Partridge
The greatest risk factor for Alzheimer’s disease (AD) is age, and changes in the ageing nervous system are likely contributors to AD pathology. Amyloid beta (Aß) accumulation, which occurs as a result of the amyloidogenic processing of amyloid precursor protein (APP), is thought to initiate the pathogenesis of AD, eventually leading to neuronal cell death. Previously, we developed an adult-onset Drosophila model of AD. Mutant Aß42 accumulation led to increased mortality and neuronal dysfunction in the adult flies. Furthermore, we showed that lithium reduced Aß42 protein, but not mRNA, and was able to rescue Aß42-induced toxicity. In the current study, we investigated the mechanism/s by which lithium modulates Aß42 protein levels and Aß42 induced toxicity in the fly model. We found that lithium caused a reduction in protein synthesis in Drosophila and hence the level of Aß42. At both the low and high doses tested, lithium rescued the locomotory defects induced by Aß42, but it rescued lifespan only at lower doses, suggesting that long-term, high-dose lithium treatment may have induced toxicity. Lithium also down-regulated translation in the fission yeast Schizosaccharomyces pombe associated with increased chronological lifespan. Our data highlight a role for lithium and reduced protein synthesis as potential therapeutic targets for AD pathogenesis.

History

Publication status

  • Published

File Version

  • Published version

Journal

Frontiers in Aging Neuroscience

ISSN

1663-4365

Publisher

Frontiers Media

Issue

190

Volume

6

Department affiliated with

  • Neuroscience Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2017-11-02

First Open Access (FOA) Date

2017-11-02

First Compliant Deposit (FCD) Date

2017-11-02

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