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.
Highlights
Aging affects every organ in the body and is an important risk factor for many progressive diseases including most neurodegenerative disorders (David et al, 2010; Niccoli and Partridge, 2012)
We show that a combretastatin analog, PNR502, can prevent and even reverse Alzheimer’s disease (AD)-like protein aggregation and associated functional/behavioral declines in Caenorhabditis elegans (C. elegans) models of Aβ1–42-induced amyloid deposition
The most effective compound tested, enhancing worm motility 17-fold, was PNR502, derived from the tubulin-binding drug combretastatin A4
Summary
Aging affects every organ in the body and is an important risk factor for many progressive diseases including most neurodegenerative disorders (David et al, 2010; Niccoli and Partridge, 2012). Regions of the brain associated with cognition and memory, are most severely impacted by AD (Frisoni et al, 1999) Genetic factors such as ApoE polymorphism, and non-genetic factors including diet, have been implicated in the risk level and etiology of AD (Ferri et al, 2005; Rizzi et al, 2014; Parcon et al, 2018). Non-pharmacological strategies commonly employed to reduce the risk of AD include supplementation of polyunsaturated, ω-3 fatty acids (Lim et al, 2005), physical activity (Roach et al, 2011), and cognitive engagement (Maci et al, 2012) None of these strategies, and no drugs currently on the market or in clinical trials, have been shown to be effective in reversal of AD dementia once it is diagnosed, nor in slowing progression of disease. Drugs that have been studied as potential therapeutic agents for AD include acetylcholinesterase inhibitors (Speck-Planche et al, 2012), monoamine oxidase inhibitors, antioxidants, N-methylD-aspartate antagonists (NMDA), and anti-inflammatory drugs (Marlatt et al, 2005; Wong, 2005; Daniels et al, 2016)
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