A Novel Microtubule-Binding Drug Attenuates and Reverses Protein Aggregation in Animal Models of Alzheimer's Disease
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 etio...
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Published in | Frontiers in molecular neuroscience Vol. 12; p. 310 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
Frontiers Research Foundation
12.12.2019
Frontiers Media S.A |
Subjects | |
Online Access | Get full text |
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Summary: | 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-Aβ
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
(
) strains that express human Aβ
in muscle or neurons, PNR502 rescued Aβ-induced disruption of motility (3.8-fold,
< 0.0001) or chemotaxis (1.8-fold,
< 0.05), respectively. Moreover, in
with neuronal expression of Aβ
, a single day of PNR502 exposure reverses the chemotaxis deficit by 54% (
< 0.01), actually exceeding the protection from longer exposure. Moreover, continuous PNR502 treatment extends nematode lifespan 23% (
≤ 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 Aβ
aggregation and prevent or reverse neurodegeneration. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewed by: Chuang Wang, Ningbo University, China; Dong Hyung Cho, Kyungpook National University, South Korea Edited by: Dong-Gyu Jo, Sungkyunkwan University, South Korea |
ISSN: | 1662-5099 1662-5099 |
DOI: | 10.3389/fnmol.2019.00310 |