Abstract
Patients with Alzheimer’s disease suffer from a decrease in brain mass and a prevalence of amyloid-β plaques. These plaques are thought to play a role in disease progression, but their exact role is not entirely established. We developed an optogenetic model to induce amyloid-β intracellular oligomerization to model distinct disease etiologies. Here, we examine the effect of Wnt signaling on amyloid in an optogenetic, Drosophila gut stem cell model. We observe that Wnt activation rescues the detrimental effects of amyloid expression and oligomerization. We analyze the gene expression changes downstream of Wnt that contribute to this rescue and find changes in aging related genes, protein misfolding, metabolism, and inflammation. We propose that Wnt expression reduces inflammation through repression of Toll activating factors. We confirm that chronic Toll activation reduces lifespan, but a decrease in the upstream activator Persephone extends it. We propose that the protective effect observed for lithium treatment functions, at least in part, through Wnt activation and the inhibition of inflammation.
Highlights
Alzheimer’s disease (AD) is an age-related disease affecting millions of people worldwide [1,2]
We observed a rescue of Aβ1−42 -CRY2-mCh (Aβ)-induced lifespan shortening through treatment with lithium but were unable to introduce lithium into embryos to test its effect on neurogenesis [11]
In an update to our previously published study, we looked at the mechanism that lithium used to extend the lifespan of Drosophila expressing Aβ1−42 -cryptochrome 2 (CRY2)-mCh
Summary
Alzheimer’s disease (AD) is an age-related disease affecting millions of people worldwide [1,2]. AD drug development has primarily been based on the amyloid cascade hypothesis, with many drugs targeting amyloid beta (Aβ) directly [6,7]. The hypothesis postulates that the extracellular deposition of Aβ leads to neuronal cell death driving AD [8], but whether these plaques are causative remains controversial, due to observations of plaques in asymptomatic individuals [9]. Aβ extracellular aggregates form macroscopic plaques that correlate with cell loss, but. Aβ can form smaller oligomers with soluble oligomers showing the highest toxicity [10]. We recently described an optogenetic method to study Aβ protein oligomerization in vivo in several model organisms [11]. Optogenetics refers to genes that are modified with a light responsive protein domain, allowing the spatial and temporal regulation of proteins [12]
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