A Novel Microtubule-Binding Drug Attenuates and Reverses Protein Aggregation in Animal Models of Alzheimer's Disease.

Abstract:

:Age-progressive neurodegenerative pathologies, including Alzheimer's disease (AD), are distinguished and diagnosed by disease-specific components of intra- or extra-cellular 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-Aβ1-42 mouse model of AD, while blunting the ability of the pro-inflammatory cytokine IL-1β to raise levels of amyloid plaque and its protein precursors in a neuronal cell-culture model. In transgenic Caenorhabditis elegans (C. elegans) strains that express human Aβ1-42 in muscle or neurons, PNR502 rescued Aβ-induced disruption of motility (3.8-fold, P < 0.0001) or chemotaxis (1.8-fold, P < 0.05), respectively. Moreover, in C. elegans with neuronal expression of Aβ1-42, a single day of PNR502 exposure reverses the chemotaxis deficit by 54% (P < 0.01), actually exceeding the protection from longer exposure. Moreover, continuous PNR502 treatment extends nematode lifespan 23% (P ≤ 0.001). Given that PNR502 can slow, prevent, or reverse Alzheimer-like protein aggregation in human-cell-culture and animal models, and that its principal predicted and observed binding targets are proteins previously implicated in Alzheimer's, we propose that PNR502 has therapeutic potential to inhibit cerebral Aβ1-42 aggregation and prevent or reverse neurodegeneration.

journal_name

Front Mol Neurosci

authors

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

doi

10.3389/fnmol.2019.00310

subject

Has Abstract

pub_date

2019-12-12 00:00:00

pages

310

issn

1662-5099

journal_volume

12

pub_type

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