A beta alters the connectivity of olfactory neuronsin the absence of amyloid plaques in vivo

摘要

The amyloid beta peptide aggregates into amyloid plaques at presymptomatic stages ofAlzheimer’s disease, but the temporal relationship between plaque formation and neuronaldysfunction is poorly understood. Here we demonstrate that the connectivity of the peripheralolfactory neural circuit is perturbed in mice overexpressing human APPsw (swedishmutation) before the onset of plaques. Expression of human APPsw exclusively in olfactorysensory neurons also perturbs connectivity with associated reductions in odour-evoked geneexpression and olfactory acuity. By contrast, olfactory sensory neuron axons project correctlyin mice overexpressing wild-type human amyloid precursor protein throughout the brain andin mice overexpressing m671V human APP, a missense mutation that reduces amyloid betaproduction, exclusively in olfactory sensory neurons. Furthermore, expression of Aβ40 orAβ42 solely in the olfactory epithelium disrupts the olfactory sensory neuron axon targeting.our data indicate that altering the structural connectivity and function of highly plastic neuralcircuits is one of the pleiotropic actions of soluble human amyloid beta.