Background: The locus coeruleus (LC), a brainstem nucleus comprising noradrenergic neurons, is one of the earliest regions affected by Alzheimer’s disease (AD). Amyloid-β (Aβ) pathology in the cortex in AD is thought to exacerbate the age-related loss of LC neurons, which may lead to cortical tau pathology. However, mechanisms underlying LC neurodegeneration remain elusive. Objective: Here, we aimed to examine how noradrenergic neurons are affected by cortical Aβ pathology in AppNL-G-F/NL-G-F knock-in mice. Methods: The density of noradrenergic axons in LC-innervated regions and the LC neuron number were analyzed by an immunohistochemical method. To explore the potential mechanisms for LC degeneration, we also examined the occurrence of tau pathology in LC neurons, the association of reactive gliosis with LC neurons, and impaired trophic support in the brains of AppNL-G-F/NL-G-F mice. Results: We observed a significant reduction in the density of noradrenergic axons from the LC in aged App NL-G-F/NL-G-F mice without neuron loss or tau pathology, which was not limited to areas near Aβ plaques. However, none of the factors known to be related to the maintenance of LC neurons (i.e., somatostatin/somatostatin receptor 2, brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3) were significantly reduced in App NL-G-F/NL-G-F mice. Conclusion: This study demonstrates that cortical Aβ pathology induces noradrenergic neurodegeneration, and further elucidation of the underlying mechanisms will reveal effective therapeutics to halt AD progression.

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BackgroundInnate immunity is dysregulated in aging and neurodegenerative diseases, and Toll‐like receptors (TLRs) play a central role in innate immune response. Nine Toll family receptors (Toll‐1 to Toll‐9) exist in Drosophila, and Toll‐9 is structurally most closely related to mammalian TLRs such as TLR1, 2, 6, 10. However, physiological roles of Toll‐9 in innate immunity and neurodegeneration are largely unknown. In this study, we examined roles of Toll‐9 in fly brains under neurodegenerative conditions.MethodWe systematically investigated potential roles of Toll‐9 in the maintenance of the brain integrity under neurodegenerative conditions, using Drosophila models of acute axon injury and human tau‐mediated neurodegeneration.ResultExpression level of Toll‐9 was very low in brains under normal condition but was dramatically increased upon acute nerve injury, suggesting a potential role of Toll‐9 in neurodegeneration. Innate immune response including induction of antimicrobial peptides and glial phagocytic activity of degenerating neurons were activated by nerve injury in fly brains, though Toll‐9 knockout did not affect these responses. Interestingly, however, Toll‐9 knockout significantly impaired activation of stress signaling cascades including c‐Jun N‐terminal kinase pathway. To ask whether Toll‐9 modify severity of neurodegeneration, we employed a fly model of tauopathy and found that Toll‐9 knockdown significantly exacerbated axon degeneration accompanied by pathological tau phosphorylation.ConclusionThese results demonstrate that Drosophila Toll‐9 confers neuroprotective effects through activation of stress kinase signaling independent of induction of innate immune genes, which may provide insights into the pathogenesis of neurodegenerative diseases.

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