Outbreak of tauopathy in the olfactory system of PS19 mice: an early marker for Alzheimer’s disease diagnosis?

Abstract

AbstractBackgroundClinical data indicate that impairment of olfactory function is an early indicator of neurodegenerative diseases, including Alzheimer’s disease (AD)(Attems et al., 2014). Our hypothesis is that typical AD lesions could appear in olfactory neurons from the olfactory epithelium (OE). The olfactory epithelium can be easily collected in human individuals (e.g., by nasal brushing), which provides an important tool to investigate the pathology in patients. Here, we address the question of the occurrence of tauopathy in the OE of transgenic mice and its correlation with pathology in the central nervous system (CNS). We use Tau P301S mice (PS19 mice), a tauopathy mouse model. These mice express human tau protein (1N4R) carrying the P301S mutation. They develop neurofibrillary tangle‐like inclusions in the cortex and hippocampus, leading to progressive neurodegeneration at eight months (Yoshiyama et al., 2007).MethodMouse samples were collected from heterozygous PS19 and wild‐type (WT) mice. Immunohistochemical staining (DAB) was used to demonstrate the presence of hyperphosphorylated human tau protein (hTau). We investigated regions of the olfactory system to correlate with data obtained in CNS regions (e.g., hippocampal formation, entorhinal cortex). Mouse heads decalcification was also implemented to preserve the olfactory epithelium structure. Western blots were performed to monitor tau levels and tau phosphorylation pattern.ResultThe hyperphosphorylated human tau protein (Ser202, Thr205) is only detected in PS19 mice sections while the endogenous murine tau protein is expressed both in WT and PS19 mice. The localization and expression of these proteins vary according to the region (OE or CNS subregions), the age (3, 6 or 9 months), and the genotype of the mice (WT or heterozygous PS19). It also seems that tau lesions may spread between brain regions that are directly connected, notably through the olfactory pathway.ConclusionIn PS19 mice, a pathological phosphorylation pattern peaked in the OE prior to vulnerable CNS regions or olfactory bulbs. We hypothesize that tau lesions appearing early in the OE may spread in the olfactory bulb and finally reach the entorhinal cortex and piriform cortex, highlighting the significance of the olfactory system investigation as an early diagnosis tool.