Reduced Autophagy in Aged Trigeminal Neurons Causes Amyloid ß Diffusion.

ABSTRACT

The relationship between oral health and the development of Alzheimer's disease (AD) in the elderly is not yet well understood. In this regard, the association between aging or neurodegeneration of the trigeminal nervous system and the accumulation of amyloid-ß(1-42) (Aß42) oligomers in the pathogenesis of AD is unknown. We focused on selective autophagy in the trigeminal mesencephalic nucleus (Vmes) and the diffusion of Aß42 oligomers with respect to aging of the trigeminal nervous system and whether the degeneration of Vmes neurons affects the diffusion of Aß42 oligomers. We used female 2- to 8-mo-old transgenic 3xTg-AD mice and AppNL-G-F knock-in mice and immunohistochemically examined aging-related changes in selective autophagy and Aß42 oligomer processing in the Vmes, which exhibits high amyloid-ß (Aß) expression. We induced degeneration of Vmes neurons by extracting the maxillary molars and examined the changes in Aß42 oligomer kinetics. Autophagosome-like membranes, which stained positive for Aß, HO-1, and LC3B, were observed in Vmes neurons of 3xTg-AD mice, while there was weak immunoreactivity of the membranes for intraneuronal Aß in AppNL-G-F mice. By contrast, there was strong immunopositivity for extracellular Aß42 oligomers with the formation of Aß42 oligomer clusters in AppNL-G-F mice. The expression of Rubicon, which indicates age-related deterioration of autophagy, increased the diffusion of Aß42 oligomer with the age of Vmes neurons. Tooth extraction increased the extracellular immunopositivity for Aß42 oligomers in AppNL-G-F mice. These results suggest that autophagy maintains homeostasis in Vmes neurons and that deterioration of autophagy due to aging or neurodegeneration leads to the diffusion of Aß42 oligomers into the extracellular space and possibly the development of AD.