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

BackgroundHyposmia in Alzheimer's disease (AD) is a typical early symptom according to numerous previous clinical studies. Although amyloid-beta (A beta), which is one of the toxic factors upregulated early in AD, has been identified in many studies, even in the peripheral areas of the olfactory system, the pathology involving olfactory sensory neurons (OSNs) remains poorly understood.MethodsHere, 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 3-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.ResultsWe 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-beta (A beta) 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.ConclusionsOur results showed that partial and asymmetrical accumulation of A beta 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.

Automated summary

Our study focused on the relationship between accumulation of amyloid-beta (A beta) in olfactory sensory neurons (OSNs) and reduced responses to odorants in 5xFAD mouse models. We found high levels of A beta in certain areas of OSNs, leading to structural damage and hyporeactivity to odorants, which may be a key factor in early AD-related hyposmia.