Fig. 8: Kynurenic acid prevents Aβ42 toxicity in a C. elegans model of AD through the action of molecular chaperones.
On treatment with 10 μM kynurenic acid, a cytosolic unfolded protein response is activated by HSF-1 and involves HSP-90, HSP-70, HSP-110, HSP40 J proteins DNJ-12 and DNJ-19, but not DNJ-13 (panels a–c). The overall fitness (bends per minute, speed and survival) in a C. elegans model of AD (GMC worms) is compromised even after treatment with 10 μM kynurenic acid in the hsf-1, daf-21, hsp-70, hsp-110, dnj-12, dnj-13, and dnj-19 knockdowns as compared to the control L4440 (c). A corresponding increase in NIAD-4 aggregates is observed (a and b). However, we do not see any aggregates on knocking down dnj-13, a class B J-protein, suggesting it may not play a role in clearing out Aβ42 aggregates. The white arrows point to NIAD-4-stained Aβ42 aggregates, which appear orange-red in color (scale bars, 80 μm). For motility assays n = ∼260–1000 animals per condition, for NIAD-4 staining assay n = 11–29 for all conditions except hsp110 knockdown, for which n = 4. All error bars represent SEM. a and c statistics were preformed using one-way ANOVA, Dunnett’s multiple comparisons test against the control L4440 AD group treated with 10 μM kynurenic acid, ****p < 0.0001; ***p < 0.001; **p < 0.01; *p < 0.05. d Schematic of the mechanism by which the metabolites clear protein aggregates by mediating a heat shock response. We propose that metabolic dysregulation may thus be a prior contributory factor to an imbalance in protein homeostasis.
