Region specific amyloid-β accumulation in the olfactory system influences olfactory sensory neuronal dysfunction in 5xFAD mice

Abstract

Background: Hyposmia in Alzheimer’s disease (AD) is a typical early symptom according to numerous previous clinical studies. Although amyloid-β (Aβ), which is one of the toxic factors upregulated early in AD, has been identified in many studies, even in the peripheral areas. The pathology involving olfactory sensory neurons (OSNs) remains poorly understood. Methods: Here, we focused on peripheral olfactory sensory neurons (OSNs) and delved deeper into the direct relationship between pathophysiological and behavioral results using odorants. We also confirmed histologically the pathological changes in three-month-old 5xFAD mouse models, which recapitulates AD pathology. We introduced a numeric scale histologically to compare physiological phenomenon and local tissue lesions regardless of the anatomical plane. Results: We observed the odorant group that the 5xFAD mice showed reduced responses to odorants. These also did not physiologically activate OSNs that propagate their axons to the ventral olfactory bulb. Interestingly, the amount of accumulated amyloid-β (Aβ) was high in the OSNs located in the olfactory epithelial ectoturbinate and the ventral olfactory bulb glomeruli. We also observed irreversible damage to the ectoturbinate of the olfactory epithelium by measuring the impaired neuronal turnover ratio from the basal cells to the matured OSNs. Conclusions: Our results showed that partial and asymmetrical accumulation of Aβ coincided with physiologically and structurally damaged areas in the peripheral olfactory system, which evoked hyporeactivity to some odorants. Taken together, partial olfactory dysfunction closely-associated with peripheral OSN’s loss could be a leading cause of AD-related hyposmia, a characteristic of early AD.

Severe histomorphological alterations in post‐mortem olfactory glomeruli in Alzheimer’s disease

“…Our PCA analysis showed apparent dissimilarities in the distribution of degeneration along the dorsal-ventral axis of the OB (Figure 6). This was in line with the findings from our previous rodent studies suggesting that region-specific degeneration and pathogenesis might be associated with the topographical organization of the OB [29]. In the murine OE, spatial cues within the tissue can direct the spatially restricted differentiation of the OSN, critical for normal olfactory function [30].…”

Smell Sensitivity in Primary Open-angle Glaucoma and Pseudoexfoliation Glaucoma

“…Taken together, partial olfactory dysfunction closely associated with loss of peripheral olfactory sensory neurons could be a leading cause of Alzheimer disease-related hyposmia, a characteristic of early Alzheimer disease. 24 Our findings confirm that smell sensitivity damage is present in XFG and likely is a contributing factor in the neurodegenerative pathogenesis of these patients.…”

“…We analyzed these similar abnormalities in glaucoma and the olfactory systems with our study. Son et al24 showed that partial and asymmetrical accumulation of amyloid-β coincided with physiologically and structurally damaged areas in the peripheral olfactory system, which evoked hyporeactivity to some odorants. Taken together, partial olfactory dysfunction closely associated with loss of peripheral olfactory sensory neurons could be a leading cause of Alzheimer disease-related hyposmia, a characteristic of early Alzheimer disease 24.…”

“…Son et al24 showed that partial and asymmetrical accumulation of amyloid-β coincided with physiologically and structurally damaged areas in the peripheral olfactory system, which evoked hyporeactivity to some odorants. Taken together, partial olfactory dysfunction closely associated with loss of peripheral olfactory sensory neurons could be a leading cause of Alzheimer disease-related hyposmia, a characteristic of early Alzheimer disease 24. Our findings confirm that smell sensitivity damage is present in XFG and likely is a contributing factor in the neurodegenerative pathogenesis of these patients.…”