Reduced Autophagy in Aged Trigeminal Neurons Causes Amyloid β Diffusion

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-β(1–42) (Aβ 42 ) oligomers in the pathogenesis of AD is unknown. We focused on selective autophagy in the trigeminal mesencephalic nucleus (Vmes) and the diffusion of Aβ 42 oligomers with respect to aging of the trigeminal nervous system and whether the degeneration of Vmes neurons affects the diffusion of Aβ 42 oligomers. We used female 2- to 8-mo-old transgenic 3xTg-AD mice and App NL-G-F knock-in mice and immunohistochemically examined aging-related changes in selective autophagy and Aβ 42 oligomer processing in the Vmes, which exhibits high amyloid-β (Aβ) expression. We induced degeneration of Vmes neurons by extracting the maxillary molars and examined the changes in Aβ 42 oligomer kinetics. Autophagosome-like membranes, which stained positive for Aβ, HO-1, and LC3B, were observed in Vmes neurons of 3xTg-AD mice, while there was weak immunoreactivity of the membranes for intraneuronal Aβ in App NL-G-F mice. By contrast, there was strong immunopositivity for extracellular Aβ 42 oligomers with the formation of Aβ 42 oligomer clusters in App NL-G-F mice. The expression of Rubicon, which indicates age-related deterioration of autophagy, increased the diffusion of Aβ 42 oligomer with the age of Vmes neurons. Tooth extraction increased the extracellular immunopositivity for Aβ 42 oligomers in App NL-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 Aβ 42 oligomers into the extracellular space and possibly the development of AD.