Inflammation Spreading: Negative Spiral Linking Systemic Inflammatory Disorders and Alzheimer's Disease

Abstract

As a physiological response to injury in the internal body organs, inflammation is responsible for removing dangerous stimuli and initiating healing. However, persistent and exaggerative chronic inflammation causes undesirable negative effects in the organs. Inflammation occurring in the brain and spinal cord is known as neuroinflammation, with microglia acting as the central cellular player. There is increasing evidence suggesting that chronic neuroinflammation is the most relevant pathological feature of Alzheimer's disease (AD), regulating other pathological features, such as the accumulation of amyloid-β (Aβ) and hyperphosphorylation of Tau. Systemic inflammatory signals caused by systemic disorders are known to strongly influence neuroinflammation as a consequence of microglial activation, inflammatory mediator production, and the recruitment of peripheral immune cells to the brain, resulting in neuronal dysfunction. However, the neuroinflammation-accelerated neuronal dysfunction in AD also influences the functions of peripheral organs. In the present review, we highlight the link between systemic inflammatory disorders and AD, with inflammation serving as the common explosion. We discuss the molecular mechanisms that govern the crosstalk between systemic inflammation and neuroinflammation. In our view, inflammation spreading indicates a negative spiral between systemic diseases and AD. Therefore, "dampening inflammation" through the inhibition of cathepsin (Cat)B or CatS may be a novel therapeutic approach for delaying the onset of and enacting early intervention for AD.

Keywords: Alzheimer’s disease; cathepsin; cytokines; macrophages; neuroinflammation; systemic inflammation; systemic inflammatory disorders.

Figure 1

Systemic inflammatory disorders influence Alzheimer’s disease (AD) by amplifying inflammation. Periodontitis, rheumatoid arthritis (RA), and gut inflammatory diseases induce/amplify systemic inflammation as well as amyloid β (Aβ) formation to induce/prolong pathological changes in the brain, including microglia-related neuroinflammation, Aβ formation, and tau hyperphosphorylation. These events contribute to the cognitive decline in AD.

Figure 2

Key roles of cathepsins in regulating systemic inflammation and neuroinflammation. Cathepsin B is involved in the production of IL-1β and TNF-α, and cathepsin S is involved in the production of IL-6 in systemic cells (monocytes/macrophages), interfacing cells (leptomeningeal cells, brain endothelial cells), and neural cells (microglia).