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

Abstract

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 (Aβ) 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 Aβ42 accumulation led to increased mortality and neuronal dysfunction in the adult flies. Furthermore, we showed that lithium reduced Aβ42 protein, but not mRNA, and was able to rescue Aβ42-induced toxicity. In the current study, we investigated the mechanism/s by which lithium modulates Aβ42 protein levels and Aβ42 induced toxicity in the fly model. We found that lithium caused a reduction in protein synthesis in Drosophila and hence the level of Aβ42. At both the low and high doses tested, lithium rescued the locomotory defects induced by Aβ42, 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.

ADrosophilaModel of Neuronopathic Gaucher Disease Demonstrates Lysosomal-Autophagic Defects and Altered mTOR Signalling and Is Functionally Rescued by Rapamycin

“…Type II, or acute neuronopathic GD, is rare but results in rapidly progressive neurological decline, with a wide spectrum of clinical signs and death in infancy or early childhood. Type III, or chronic neuronopathic GD, is a more slowly progressive disorder with neurological features, including eye movement abnormalities, myoclonic epilepsy, ataxia, and dementia (Sidransky, 2004). There are currently no therapies available that target the neuronal pathology associated with GD because existing treatments, such as recombinant enzyme replacement therapy, fail to permeate the blood-brain barrier (Cox, 2010).…”

Genetics and Pharmacology of Longevity

“…4E-BP downstream of mTORC1 seems to be required for the life span extending effect of rapamycin depending on the genetic background (Bjedov et al, 2010;Partridge et al, 2011). This was surprising given the predominant role of 4E-BP in the regulation of protein translation (Thoreen et al, 2012), which seems to be a key molecular process for life span extension in invertebrates (Hansen et al, 2007;Kaeberlein et al, 2005;Rallis et al, 2013;Sofola-Adesakin et al, 2014;Steffen et al, 2008;Syntichaki et al, 2007). While one group reported that 4E-BP null flies do not respond to DR (Zid et al, 2009), indicating that 4E-BP is required for life span extension by DR, another group showed that 4E-BP is dispensable for the life span extending properties of DR in flies .…”

“…However, neither of these mechanisms have been shown to mediate life span extension by lithium. Lithium was recently reported to extend the chronological life span of fission yeast (Sofola-Adesakin et al, 2014). It has been reported to extend life span in C. elegans by three independent groups (McColl et al, 2008;Tam, Gruber, Ng, Halliwell, & Gunawan, 2014;Zarse et al, 2011) and one report demonstrated that low doses of lithium reduce mortality in Drosophila (Matsagas et al, 2009).…”

The promises of neurodegenerative disease modeling

“…This is illustrated by three recent examples. One is the finding that lithium suppresses the pathological effects of accumulation of the Ab peptide in a model of Alzheimer's disease by reducing protein translation [52]. Another is the demonstration of the therapeutic potential of methylene blue that has been shown to reduced neurodegeneration and Hunttingtin aggregation in a fly HD model [53] and rescue heart defects in a fly model of Friedreich's ataxia [45].…”