Nevertheless, overexpression from the B secretase like protein resulted in cleavage of dAPPl making a fragment corresponding to your human AB peptide Interestingly, this fragment is also able to aggregate and induces age dependent behavioral deficits and neurodegeneration As well as endogenous AB production, transgenic flies are generated to examine human AB42 induced toxicity and neurodegeneration Greeve and co workers produced a triple transgenic fly expressing human APP human B secretase and Drosophila secretase presenilin with level mutations corre sponding to familial AD mutations N141I, L235P and E280A These flies designed age dependent neurodegenerative phenotypes this kind of as photoreceptor cell reduction, severe degeneration of their projecting axons and early lethality. Co expression of hAPP and hBACE favored the processing of the increased glycosylated species of hAPP in Drosophila resulting in AB40 and AB42 peptide forming plaques in transgene expressing tissue.
Plaque deposition precedes the onset of neurodegeneration and coexpression of mutant dPsn results in acceleration of photoreceptor degeneration The described triple transgenic model clearly demonstrates the similarities amongst the biochemical pathways induced by AB42 deposition b-AP15 in flies and people. A more direct approach to investigate AB42 induced toxicity was used by Crowther and co staff They fused AB40 42 peptides for the signal peptide of endogen ous Drosophila necrotic gene sequence ensuring secretion Utilizing the UAS Gal4 inducible gene expression procedure the authors created transgenic flies permitting the spatiotemporal expression of AB40 and AB42. Because the expressed AB40 42 correspond towards the peptides created by amyloidogenic processing of APP, influences that may consequence from APP processing are prevented.
These flies possess the key benefit of the direct assessment of AB toxicity. Neuronal expression of AB42 induced neurotoxicity, lo otion defects and lowered lifespan. Also, intra and extracellular accumulation of AB42 peptides was observed. Overexpression of AB42, acknowledged to improve the charge of AB42 heparin aggregation exacerbated the observed phenotypes Extensive investigation of molecular mechanisms resulting in modifications in synaptic transmission and protein position with the presynaptic lively zone revealed that AB42 expression impacted axonal transport of mitochondria and resulted in depletion of mitochondria from your presynaptic lively zone Intra neural accumulation of AB42 was shown to cut back synaptic vesicle release probability just before bouton reduction Patch clamp evaluation revealed a depression of cholinergic synapses upon AB42 expression.