Impairment in re-learning of olfactory behaviors in mice expressing intracellular amyloid-β protein oligomers

Abstract

Background

The accumulation of amyloid-β (Aβ) protein is a plausible candidate for the primary cause of Alzheimer's disease (AD). In addition to extracellular deposition, intracellular accumulation of Aβ oligomers is thought to occur during early-stage AD. Considering that olfactory dysfunction is an early event in AD, analyses of intracellular Aβ deposition in the olfactory system could provide insights into disease mechanisms and therapeutic strategies, particularly for early-stage AD.

Objective

We examined the olfactory behaviors of transgenic mice expressing intracellular Aβ-green fluorescent protein (GFP) fusion protein oligomers and investigated the manifestation of any abnormalities in mature and young adult stages.

Methods

In 6–7-month-old and 2–3-month-old transgenic mice, expression of Aβ-GFP was histologically examined in the fixed brains. The mice's olfactory behaviors including odor detection, odor discrimination and odor-associated learning and memory were examined.

Results

Histological analysis confirmed intracellular Aβ-GFP accumulation in brain regions related to olfaction, including the olfactory bulb, olfactory cortex, and orbitofrontal cortex. In 6–7-month-old mice, odor detection and discrimination abilities, as well as odor-reward association learning and long-term memory, were not significantly affected. However, the mice exhibited impaired re-learning of the odor-reward association, in which the initial association of two different odors with or without a sugar reward was subsequently reversed. This behavioral phenotype also was observed in 2–3-month-old mice.

Conclusions

These findings indicate that mice expressing intracellular Aβ oligomers experience early-life olfactory disturbances, highlighting their potential utility in studying olfactory dysfunction in early-stage AD.