Wnt Signaling Rescues Amyloid Beta-Induced Gut Stem Cell Loss

Abstract

Patients with Alzheimer’s disease suffer from a decrease in brain mass and a prevalence of amyloid- 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- 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.

Combining stem cell rejuvenation and senescence targeting to synergistically extend lifespan

“…As these flies were expressing the factors ubiquitously, we could not use the esg>GFP marker for ISCs and instead used an endogenously GFP-tagged allele of the Wnt responsive β-catenin gene [38]. ISCs show higher levels of cytoplasmic β-catenin protein making them readily identifiable, but in addition other cell types in the epithelium show junctional β-catenin [45]. We visualized ISCs in gastric epithelia of flies with cycling expression of OKSM, Sen or both at four weeks (Figure 5A-5D), eight weeks (Figure 5G-5J), and twelve weeks (Figure 5M-5P).…”

“…The 3 mm glass bottom dish was then mounted onto the Zeiss LSM800 (Carl Zeiss AG, Germany) for imaging. For each construct, midguts from at least 3 flies were dissected and imaged at the 25% percentile from the anterior midgut [45]. The SA-β-gal activity was visualized using a Senescent Cells Staining Kit (CellEvent ™ Senescence Green Detection Kit, C10850, Invitrogen).…”

Preconception maternal gut dysbiosis affects enteric nervous system development and disease susceptibility in offspring

“…Interestingly, EDNRB mRNA expression was upregulated, possibly as a compensatory mechanism. Moreover, blocking the Wnt pathway disrupts the normal proliferation and differentiation of colonic epithelial tissue 31 .…”

Combining Stem Cell Rejuvenation and Senescence Targeting to Synergistically Extend Lifespan

“…The 3mm glass bottom dish was then mounted onto the Zeiss LSM800 (Carl Zeiss AG, Germany) for imaging. For each construct, midguts from at least 3 flies were dissected and imaged at the 25% percentile from the anterior midgut ( 63 ).…”