Olfactory deprivation promotes amyloid β deposition in a mouse model of Alzheimer’s disease

Abstract

Olfactory dysfunction is regarded as an early marker for Alzheimer’s disease (AD). Slowly progressing AD pathology is interpreted to impair cognition and olfactory sensation independently, while olfactory deficits emerge earlier. The present experiments tested the possibility that olfactory impairment may worsen cognition or AD pathology using 3xTg AD model mice with olfactory bulbectomy (OBX). In open-field tests, OBX was shown to increase anxiety-like behavior in both wild-type (WT) and AD model mice, and hyperactivity was induced in WT mice only. Spatial memory, assessed by the Morris water maze (MWM) test, was impaired in WT but not AD mice. Object memory, assessed by the novel object recognition test, was not changed by OBX either in WT or AD mice. Densitometry of Aβ plaques stained with 6E10 and anti-Aβ42 antibodies was carried out in sections containing the hippocampal formation obtained from AD mice aged 12 and 18 months. The plaque area was larger in the OBX than in the sham group at 12 months. At 18 months, there was also difference in the plaque area. Given that Aβ plaques emerge in 3xTg mice relatively later (>9 months of age) than in other models, OBX in 3xTg mice appears to exacerbate Aβ pathology at the early phase of Aβ emergence, implying a causative link of smell loss to AD pathogenesis. The accelerated Aβ plaque formation by OBX was accompanied by microglial activation. Early intervention to smell loss may be beneficial for AD control.