Differential neurotoxicity caused by mild overexpression of amyloid peptides associated with human dementias in Drosophila melanogaster

MARCORA M.S; FERNANDEZ GAMBA, A.; AVENDAÑO- VAZQUEZ. L.A; ROTONDARO, C; VIDAL, R; MORELLI, L; CERIANI M.F; CASTAÑO. E.M

Cancun

Congreso; The 24th Biennial Meeting of the International Society for Neurochemistry and the American Society for Neurochemistry, ISN-ASN; 2013

Alzheimer s disease (AD) is characterized by the dysfunction of aged neurons of specific types and the progressive accumulation of amyloid Beta (ABeta) and tau, major components of plaques and neurofibrillary tangles (NFT), respectively. Familial British and Danish dementias (FBD and FDD) are autosomal dominant neurodegenerative diseases associated to accumulation of amyloid peptides. Internal proteolysis of the precursor protein carrying different mutations leads to the release of ABri and ADan, which are highly amyloidogenic. Several features are common to FBD, FDD and AD: progressive dementia, amyloid deposition in the CNS, accumulation of complement proteins and their pro-inflammatory activation products and NFT with hyper phosphorylated tau. Drosophila melanogaster is a suitable animal model to study human neurodegenerative disorders. To compare the effects caused by accumulations of different amyloid peptides, we generated transgenic Drosophila lines that over-express ABeta42, ABri, ADan and p23 (a non-amyloidogenic peptide as control) using the Gal4/UAS binary system. Site-directed insertion of the transgenes should ensure similar levels of expression. We confirmed the expression of the peptides by RT-PCR, Western Blot and Inmunohistochemistry. When 2 copies of the peptides were over-expressed in the eyes using GMR-Gal4, ABri and ADan caused a moderate rough eye phenotype which was absent in the p23 control. Histological analysis of paraffin sections from adult heads showed specific staining of the peptides in the retina, as well as amyloid deposits. The over-expression of the peptides in the CNS, using elav-Gal4 driver, caused locomotor dysfunction which was dose-dependent and progressive with age. Flies expressing 2 copies of ADan showed an accelerated decline in their climbing behavior at 7 days post-eclosion related to control flies. The climbing ability of flies expressing ABeta42 and ABri was reduced significantly at 15 days post-eclosion. These results indicate that these amyloid peptides have differential toxic effects on Drosophila tissues, and may be due to the aggregation ability of each peptide, ADan being more amyloidogenic than ABeta42 and ABri, and /or the differential neuronal susceptibility to each peptide.