siRNA targeted against amyloid precursor protein impairs synaptic activity in vivo

The amyloid precursor protein (APP) plays a central role in Alzheimer's disease (AD) pathogenesis through its cleavage leading to the accumulation of the peptide betaA4. Diffusible oligomeric assemblies of amyloid beta peptide are thought to induce synaptic dysfunction, an early change in AD. We tested the hypothesis that a reduction in presynaptic APP could itself lead to a decrease in synaptic efficacy in vivo. Twenty-four hours after intraocular injection, siRNA targeted against APP accumulated in retinal cells and the APP in retinal terminals in the superior colliculus was significantly reduced. Surprisingly, the amyloid precursor-like protein 2 (APLP2) was reduced as well. Functional imaging experiments in rats during visual stimulation showed that knockdown of presynaptic APP/APLP2 significantly reduced the stimulation-induced glucose utilization in the superior colliculus. Our results suggest that perturbations in the amount of APP/APLP2 axonally transported to, and/or in their turnover in the nerve terminal alter synaptic function and could be a pathogenic mechanism in AD.