Aβ alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo

The Aβ peptide aggregates into amyloid plaques at presymptomatic stages of Alzheimer's disease, but the temporal relationship between plaque formation and neuronal dysfunction is poorly understood. Here, we demonstrate that the connectivity of the peripheral olfactory neural circuit is perturbed in mice overexpressing human APPsw (Swedish mutation) prior to the onset of plaques. Expression of hAPPsw exclusively in olfactory sensory neurons (OSNs) also perturbs connectivity with associated reductions in odor-evoked gene expression and olfactory acuity. By contrast, OSN axons project correctly in mice overexpressing wild type human APP throughout the brain and in mice overexpressing human APPmv, a missense mutation that reduces Aβ production, exclusively in OSNs. Furthermore, expression of Aβ40 or Aβ42 solely in the olfactory epithelium disrupts OSN axon targeting. Our data indicate that altering the structural connectivity and function of highly plastic neural circuits is one of the pleiotropic actions of soluble human Aβ.