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Article Dans Une Revue Neurobiology of Aging Année : 2006

siRNA targeted against amyloid precursor protein impairs synaptic activity in vivo

Résumé

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 ␤A4. 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.

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a S Herard, L. Besret, André Dubois, J. Dauguet, T. Delzescaux, et al.. siRNA targeted against amyloid precursor protein impairs synaptic activity in vivo. Neurobiology of Aging, 2006, 27 (12), pp.1740-1750. ⟨10.1016/j.neurobiolaging.2005.10.020⟩. ⟨hal-02155634⟩
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