PgmNr W4068: Investigation of medicinal and therapeutic effects of boronic acid compounds in an Alzheimer’s Disease model of Caenorhabditis elegans.

Authors:
D. Flaherty; W. Lawless; L. Hall; A. McKelvy; D. Makholm; J. Larkin


Institutes
Eckerd College, St. Petersburg, FL.


Keyword: Longevity

Abstract:

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease which affects an estimated 44 million people over the age of 65 (Alzheimer’s Disease International). The aggregation of amyloid-β (Aβ1-42) into “senile plaques” is a hallmark cellular pathology of the disease.  Accumulation of Aβ1-42 is a main target of therapeutic research due to the caustic and toxic nature of these aggregates. The C.elegans transgenic model GMC101 expresses full length human Aβ1-42 in its body wall muscles, which aggregates and leads to permanent and severe paralysis, allowing for robust behavioral outcome to score for plaque burden.  Similarly, strain CL2006 is an abundant expresser of Ab3-42 and provides a useful model for aggregate analysis.

Boronic acid compounds have been utilized in a wide range of drug therapies because of their high level of specificity and ability to interact with the proteasome.  To date, these compounds have not been extensively studied in AD related pathology. We have hypothesized several potential benefits of boronic acid and boronic ester compounds to AD pathology, including enzyme inhibition and proteasome interaction. Our preliminary data indicate that boronic ester compounds have a major impact on the toxicity of Aβ1-42 by significantly delaying paralysis in the GMC101 model. This result has been further supported via fluorescence microscopy with the use of the fibrillary stain Thioflavin T (ThT), which identified a substantial decrease in Aβ1-42 aggregation compared to the controls. To further confirm our findings, we have also begun to conduct in vivo staining in live animals using the lipophilic-congo red derivative X-34, a more sensitive detector of of Aβ aggregates.



Wormbase Genetic Index
1. GMC101
2. CL2006