Neuroinflammation in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large socioeconomic and personal costs. Increasing age is associated with an increase in low-grade chronic inflammation (inflammaging) that may contribute to the neurodegenerative process in AD. Although the exact mechanisms remain unclear, aberrant elevation of reactive oxygen and nitrogen species (RONS) levels from several endogenous and exogenous processes in the brain may not only affect cell signaling, but also trigger cellular senescence, inflammation, and pyroptosis. Moreover, a compromised immune privilege of the brain that allows the infiltration of peripheral immune cells and infectious agents may play a role. Additionally, meta-inflammation as well as gut microbiota dysbiosis may drive the neuroinflammatory process. Considering that inflammatory/immune pathways are dysregulated in parallel with cognitive dysfunction in AD, elucidating the relationship between the central nervous system and the immune system may facilitate the development of a safe and effective therapy for AD. We discuss some current ideas on processes in inflammaging that appear to drive the neurodegenerative process in AD and summarize details on a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without affecting defense mechanisms against pathogens and tissue damage.

Keywords: Alzheimer’s disease; DAMPs; SASP; astrocytes; immunosenescence; inflammasome; microglia; mitochondria; neuroinflammation.

Figure 1

Schematic representation of the proposed causes of neuroinflammation in Alzheimer’s disease (AD). Age-related release of damage-associated molecular patterns (DAMPs) such as Aβ, extracellular ATP, and cell debris such as circulating mitochondrial DNA, which are capable of interacting with the Nod-like receptor 3 (NLRP3), creates an oxidative and neuroinflammatory environment through the excessive production and release of pro-inflammatory cytokines and reactive oxygen and nitrogen species (RONS). Further, mitochondrial reactive oxygen species (mtROS) and senescence-associated secretory phenotype (SASP) factors from the senescent cells, which also drive senescence in nearby cells, produce pro-inflammatory cytokines. This culminates in neuroinflammation and neuronal apoptosis.

Figure 2

The interactions between aging and neuroinflammation in the pathogenesis of AD. With age, several cellular and molecular mechanisms elicit chronic sterile low-grade inflammation. This interaction of exogenous and endogenous risk stimuli, including defective autophagy, mitochondrial dysfunction, oxi-inflammation, cellular senescence, meta-inflammation, gut microbiota dysbiosis, and complement, triggers neuroinflammation. The resulting inflammatory mediator secreted drives the pathophysiological mechanisms of AD.