Age-progressive neurodegenerative pathologies, including Alzheimer’s disease (AD), are distinguished and diagnosed by disease-specific components of intra- or extracellular aggregates. Increasing evidence suggests that neuroinflammation promotes protein aggregation, and is involved in the etiology of neurological diseases. We synthesized and tested analogs of the naturally occurring tubulin-binding compound, combretastatin A-4. One such analog, PNR502, markedly reduced the quantity of Alzheimer-associated amyloid aggregates in the BRI-Ab1–42 mouse model of AD. In transgenic C. elegans strains that express human Ab1–42 in muscle or neurons, PNR502 rescued Ab-induced disruption of motility (3.8-fold, P < 0.0001) or chemotaxis (1.8-fold, P < 0.05), respectively.
Methods
Transgenic C. elegans strain (CL4176), capable of induction to express Ab1–42 in muscle were induced at the L4/adult transition, by upshift from 20ºC to 25.5ºC, and then maintained for 41 hours on solid media with the tested compounds (at 10 mM) or vehicle. For motility assay, worms were placed 20 per well, in S basal medium in a flat-bottom 96-well plate. Movement was monitored with WMicrotracker device.
Results
We synthesized analogs of several plant-derived drugs, in search of novel agents that delay or prevent aggregation mediated diseases. We initially screened molecules from three drug libraries, in a C. elegans strain that expresses low levels of human Ab1–42 in muscle, resulting in age-dependent deposition of amyloid plaque and a progressive loss of motility. The most effective compound tested, enhancing worm motility17-fold, was PNR502, derived from the tubulin-binding drug combretastatin A4.
Front Mol Neurosci. 2019 Dec 12;12:310. doi: 10.3389/fnmol.2019.00310. eCollection 2019.
Kakraba S, Ayyadevara S, Penthala NR, Balasubramaniam M, Ganne A, Liu L, Alla R, Bommagani SB, Barger SW, Griffin WST, Crooks PA, Shmookler Reis RJ