PgmNr D1358: Investigate the Effects of Cyclopamine on Drosophila melanogaster Model of Alzheimer’s Disease.

Authors:
P. T. Nguyen 1 ; M. Sharoni 1 ; N. Latcheva 2 ; M. Krach 1 ; K. Innamorati 2 ; A. Saunders 1 ; D. Marenda 1,2,3


Institutes
1) Drexel University Department of Biology, Philadelphia, PA; 2) Molecular Cell Biology and Genetics Program, Drexel University College of Medicine, Philadelphia, PA; 3) Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA.


Keyword: neural degeneration

Abstract:

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in older adults. AD pathology includes formation of amyloid plaques, a major component of which is the Amyloid β peptide (Aβ) generated from sequential proteolytic cleavage of Amyloid precursor protein (APP) by β- and γ-secretases. Aβ accumulation is neurotoxic and leads to synaptic dysfunction, neuronal death, and learning and memory defects. Our lab identified the Smoothened receptor of the Sonic Hedgehog signaling pathway in a genetic screen as a regulator of APP metabolism. In a later study, Cyclopamine (an antagonist of the Smoothened receptor) was shown to alter the subcellular trafficking of APP C-terminal fragments (substrates for γ-secretase cleavage) in HeLa cells and primary rat cortical neurons. Thus, we hypothesized that Cyclopamine would have a similar mechanism of action in an in vivo AD model. To test this, we used transgenic Drosophila melanogaster which overexpress human APP and β-secretase in all postmitotic neurons under the control of the Gal4-UAS system. We showed that Cyclopamine rescues a number of defective phenotypes observed in our AD Drosophila model including external morphology, larval locomotion, adult motor reflex, and neuroanatomy. These data suggest Cyclopamine can be investigated further for AD therapeutics.