Comparisons of neuroinflammation, microglial activation, and degeneration of the locus coeruleus-norepinephrine system in APP/PS1 and aging mice

Song Cao,Hongxin Dong,Daniel W Fisher,Guadalupe Rodriguez,Tian Yu

doi:10.1186/s12974-020-02054-2

Abstract

BackgroundThe 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. 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. Though the LC-NE is likely to influence microglial dynamics, it is unclear how these systems change with AD compared to otherwise healthy aging.MethodsIn 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.ResultsOur 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. 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. 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.ConclusionThese 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.

Highlights

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 [1], chronic pain [2], and seizures [3]
PS1 mice Activated microglia have been shown to play a critical role in AD pathogenesis, and Iba-1 expression in microglia is often used as a marker for activated microglia
The expression of Iba-1 was more pronounced in 12-month-old APP/ PS1 mice compared to 24-month-old Wild type (WT) mice in prefrontal cortex (PFC) (5.42 ± 0.23 vs 12.62 ± 0.79, P < 0.0001, Fig. 1b), Anterior cingulate cortex (ACC) (P < 0.0001, Fig. 1c), dentate gyrus (DG) (P < 0.0001, Fig. 1d), and CA3 (P = 0.044, Fig. 1e), suggesting AD pathogenesis has a greater effect on microglial activation than otherwise healthy aging

Summary

Introduction

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 [1], chronic pain [2], and seizures [3]. DAM cross-seed Aβ oligomers and plaques [9, 10] enhance tau spreading and taudriven neurodegeneration and astrogliosis [11,12,13] and facilitate synapse loss [14]. While these DAM are located around the neuropathological hallmarks of AD and are well correlated with cognitive decline [15, 16], it is still unclear how DAM influence other AD symptoms. Though the LC-NE is likely to influence microglial dynamics, it is unclear how these systems change with AD compared to otherwise healthy aging

Methods

Results

Discussion

Conclusion