NE suppressed Aβ-induced cytokine and chemokine production, while induced degeneration of noradrenergic neurons increased expression of inflammatory mediators in APP-transgenic mice. Similarly, β-adrenergic agonism in microglia reduced TNF-α, IL-6, and free radical expression induced by LPS or prostaglandin E2 and protected co-cultured cortical neurons from death. The mechanism of these anti-inflammatory effects seem to be through activation of β 1 and β 2 receptors, as pharmacological agonism of these receptors in hippocampal slice cultures reduced lipopolysaccharide (LPS)-induced microglial activation and TNF-α, IL-6, and MCP-1 production. Functionally, microglia are regulated by NE, as NE inhibits microglial activation and reduces pro-inflammatory factors such as IL-6 and TNF-α. Interestingly, microglia are well equipped to respond to NE signaling by expressing α 1A, α 2A, β 1, and β 2 receptors. While some degeneration of LC neurons also occurs in normal aging, an estimated 50 to 60% loss of LC-NE neurons is observed in AD patients, far out-pacing LC loss seen with healthy aging. As the main source of norepinephrine (NE) in the CNS, the LC plays critical roles in a variety of brain functions, including cognition, attention, emotion, the sleep-wake cycle, and regulation of chronic pain. Though neurodegeneration in cortical and hippocampal areas has been well studied in AD, the sub-cortical locus coeruleus (LC) is actually one of the first brain regions to undergo degeneration in AD pathogenesis. Further, DAM are not only found in neural regions classically associated with AD but also in the spinal cord, where it is unclear how they may exacerbate non-cognitive AD symptoms, such as chronic pain. While these DAM are located around the neuropathological hallmarks of AD and are well correlated with cognitive decline, it is still unclear how DAM influence other AD symptoms. DAM cross-seed Aβ oligomers and plaques enhance tau spreading and tau-driven neurodegeneration and astrogliosis and facilitate synapse loss. Activated microglia have a nuanced role in AD and highly depend on the disease stage as well as particular activation pattern. One pathological change noted in the AD brain is microglial activation in the form of disease-associated microglia (DAM), leading to aberrant expression of proinflammatory cytokines in a well-characterized pattern. The cellular and biochemical mechanisms that may contribute to the severity of chronic pain in AD are not well understood. Chronic pain in particular also increases with aging, but AD seems to exacerbate chronic pain both quantitatively and qualitatively. Though Alzheimer’s disease (AD) is primarily characterized by progressive memory decline, numerous other symptoms appear during the course of the disease, including neuropsychiatric symptoms, chronic pain, and seizures. These results suggest that elevated neuroinflammation and microglial activation in the brain and spinal cord of APP/PS1 mice correlate with significant degeneration of the LC-NE system. Notably, the degree of microglial activation, LC-NE nerve fiber loss, and NET reduction in the brain and spinal cord were more severe in 12-month-old APP/PS1 compared to 12- and 24-month-old WT mice. LC-NE neuron and fiber loss as well as reduced norepinephrine transporter (NET) expression was more evident in APP/PS1 mice, although NE levels were similar between 12-month-old APP/PS1 and WT mice. Our results demonstrated increased expression of inflammatory cytokines and microglial activation observed in the cortex, hippocampus, and spinal cord of APP/PS1 compared to WT mice. In this study, we evaluated the dynamic changes of neuroinflammation and neurodegeneration in the LC-NE system in the brain and spinal cord of APP/PS1 mice and aged WT mice using immunofluorescence and ELISA. Though the LC-NE is likely to influence microglial dynamics, it is unclear how these systems change with AD compared to otherwise healthy aging. During early AD pathogenesis, one of the first areas of degeneration is the locus coeruleus (LC), which provides broad innervation of the central nervous system and facilitates norepinephrine (NE) transmission. The role of microglia in Alzheimer’s disease (AD) pathogenesis is becoming increasingly important, as activation of these cell types likely contributes to both pathological and protective processes associated with all phases of the disease.
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