At ages less than 3 weeks, the latency of evoked dorsal longitudinal flight muscle (DLM) and Tergotrochanter muscle (TTM) excitatory junctional potentials (EJPs) is about 0.8ms in flies expressing one or two copies of Hsap\APP1-42.Scer\UAS.T:SS-nec under the control of Scer\GAL4OK307 (compared to 1.2ms in controls). At ages over 3 weeks, the latencies of evoked DLM and TTM EJPs in flies expressing one or two copies of Hsap\APP1-40.Scer\UAS.T:SS-nec are significantly increased, in a dosage-dependent manner, demonstrating a slowing of neurotransmission in both the TTM and DLP pathways. In some 2xHsap\APP1-42.Scer\UAS.T:SS-nec flies over 3 weeks old, neither DLM nor TTM EJPs are evoked by brain stimulation, demonstrating a loss of neurotransmission. Failure of neurotransmission in the TTM pathway is more frequent than in the DLM pathway, suggesting that the TTM pathway is more susceptible to the intraneuronal accumulation of Hsap\APP, although the TTM pathway is relatively shorter and contains fewer synapses.
Flies expressing Hsap\APPScer\UAS.T:nec under the control of Scer\GAL4elav-C155 display significantly increased survival when cultured on food containing 1000μ YM-F24 (an iron-specific metal chelator).
Expression of two copies of Hsap\APP1-42.Scer\UAS.T:SS-nec under the control of Scer\GAL4shot-OK307 significantly accelerates the age-related decline in the flight ability of adult flies and shortens adult lifespan relative to controls. It also hastens the age-related decline in neurotransmission functionality: the success rate of eliciting excitatory junction potentials (EJP) in the dorsal longitudinal muscle (DLM) fibers in response to brain stimulation is much lower compared to controls and decreases more steeply with the number of stimulations and enhances the age-progressive increase in synaptic transmission fatigue rate. The neurotransmission along the tergotrochanteral muscle pathway is affected to a much lesser degree. Expression of two copies of Hsap\APP1-42.Scer\UAS.T:SS-nec also leads to age-progressive depletion of synaptic vesicles, their increased size and heterogeneity, depletion of presynaptic mitochondria (as well as slightly higher frequency of damaged mitochondria) and accumulation of presynaptic vacuoles compared to age-matched controls. Neither the mean area of the mitochondria nor the number of boutons on the neuromuscular junction is significantly changed by expressing either two or just one copy of Hsap\APP1-42.Scer\UAS.T:SS-nec. Expression of just one copy also has much more subtle effect on flight capability of adult flies compared to when two copies are used, and it does not significantly change adult survival rate but it does reduce the DLM EJP success rate.