Amyloid peptides associated with human dementias, Aβ42, ABri and ADan cause differential neurotoxicity in Drosophila brain

MARCORA MS; FERNANDEZ GAMBA A; VIDAL R; MORELLI L; CERIANI MF; CASTAÑO EM

Washington

Congreso; 44th Society for Neuroscience Annual Meeting; 2014

Society for Neuroscience

Several neurodegenerative diseases share common features such as their clinical progression with age, synaptic abnormalities followed by neuronal loss and the presence of amyloid deposit in the brain. Alzheimer?s disease (AD), the most common cause of dementia, is characterized by the aged-associated dysfunction of cholinergic neurons and the progressive accumulation of amyloid β (Aβ) and hyperphosphorylated tau, major components of senile plaques and neurofibrillary tangles (NFT), respectively. Familial British and Danish dementias (FBD and FDD) are autosomal dominant neurodegenerative disorders associated to the accumulation of amyloids ABri and ADan, respectively. Internal proteolysis of the precursor protein BRI2 carrying different mutations leads to the release of ABri and ADan, which are highly amyloidogenic in vitro as compared to Aβ. Drosophila melanogaster is a suitable animal model to study the relationship between different amyloids and their specific neurodegenerative and behavioral phenotype. We generated transgenic Drosophila lines that over-express human amyloids Aβ42, ABri and ADan, respectively, or a control peptide Bri2-23 (the non-amyloidogenic product of the internal proteolysis of wild type BRI2) using the Gal4/UAS binary system. Pan-neuronal expression revealed an age-dependent toxicity of amyloids as determined by the ability of flies to climb in a geotaxis paradigm when compared to Bri2-23. ADan-expressing flies displayed a significant impairment in climbing ability at 7 days post eclosion (p.e) (p< 0.001), while ABri and Aβ42 showed a significant toxicity at 15 and 21 days respectively (p<0.01). Histological analysis of paraffin brain sections showed thioflavine-S-negative accumulation of amyloids peptides along with mild vacuolization. In addition, we analyzed the levels of Bruchpilot (Brp), a protein involved in clustering and vesicle release at the presynaptic active zones. Western blots from fly heads showed an age-dependant reduction of Brp in amyloid-expressing as compared to controls. At 7 days p.e. no differences were found while at 21 days Brp levels in amyloid-expressing flies were reduced (approximately a 20%) as compared to Bri2-23 control flies. Our results indicate that different amyloids display differential neurotoxicity in the CNS. However, all of them appear to affect synaptic transmission in an aged-dependent manner. These Drosophila models will allow a systematic and unambiguous assessment of differences and similarities in the mechanisms of toxicity of diverse amyloid peptides associated with dementia.