The role of peripheral inflammatory insults in Alzheimer's disease: a review and research roadmap

Abstract

Peripheral inflammation, defined as inflammation that occurs outside the central nervous system, is an age-related phenomenon that has been identified as a risk factor for Alzheimer's disease. While the role of chronic peripheral inflammation has been well characterized in the context of dementia and other age-related conditions, less is known about the neurologic contribution of acute inflammatory insults that take place outside the central nervous system. Herein, we define acute inflammatory insults as an immune challenge in the form of pathogen exposure (e.g., viral infection) or tissue damage (e.g., surgery) that causes a large, yet time-limited, inflammatory response. We provide an overview of the clinical and translational research that has examined the connection between acute inflammatory insults and Alzheimer's disease, focusing on three categories of peripheral inflammatory insults that have received considerable attention in recent years: acute infection, critical illness, and surgery. Additionally, we review immune and neurobiological mechanisms which facilitate the neural response to acute inflammation and discuss the potential role of the blood-brain barrier and other components of the neuro-immune axis in Alzheimer's disease. After highlighting the knowledge gaps in this area of research, we propose a roadmap to address methodological challenges, suboptimal study design, and paucity of transdisciplinary research efforts that have thus far limited our understanding of how pathogen- and damage-mediated inflammatory insults may contribute to Alzheimer's disease. Finally, we discuss how therapeutic approaches designed to promote the resolution of inflammation may be used following acute inflammatory insults to preserve brain health and limit progression of neurodegenerative pathology.

Keywords: Cytokines; Dementia; Infection; Inflammation; Neuro-immune axis; Neuroinflammation; Peripheral inflammation; Systemic inflammation.

Fig. 1

Contributing conditions and potential mechanisms underlying the relationship between inflammation and Alzheimer’s disease. The outer circle specifies several acute and chronic conditions that have been hypothesized to influence risk for Alzheimer’s disease and related dementias. The inner circle specifies potential biological mechanisms by which acute and chronic inflammatory conditions may influence target cells within the brain, specifically microglia. The biological processes initiated by acute and chronic inflammatory conditions are hypothesized to converge on common signaling pathways that can in turn prime and activate microglia via the neuro-immune axis

Fig. 2

Peripheral inflammation affects brain function via the neuro-immune axis. Levels of inflammatory proteins increase in the blood after an inflammatory insult. Circulating inflammatory proteins can activate endothelial cells, which then upregulate cellular adhesion molecules, such as ICAM1 and VCAM1. Cellular adhesion molecules tether myeloid cells, leading to further endothelial activation and vascular inflammation. As part of this process endothelial cells activate pro-inflammatory transcription factors, causing an increased expression of pro-inflammatory factors in the brain. Circulating inflammatory proteins in blood (e.g., TNF-ɑ) can cause breakdown in blood–brain barrier tight junctions, allowing for increased flow of blood proteins into the brain parenchyma and CSF. Inflammatory proteins in blood can also be transported into the brain via receptor-mediated transcytosis, and with increasing age, non-specific caveolar transcytosis. Outside the cerebral microvessel, activation of perivascular macrophages can further enhance blood–brain barrier permeability. Comprised of fenestrated capillaries, circumventricular organs (listed in red text) are gaps within the blood–brain barrier that allow for direct communication between molecules circulating in the blood, including cytokines, and target cells within the brain. In the context of peripheral inflammation, the vagus nerve sends inflammatory signals from the gut, liver, lungs, and other organs to the brain. The solitary nucleus relays these peripherally derived inflammatory signals to the hypothalamus, thalamus, and other brain regions in a manner which can promote glial expression of inflammatory proteins and receptors. Abbreviations: AP, area postrema; ICAM1, intercellular adhesion molecule 1; IL-1β, interleukin 1 beta; IL1R1, interleukin 1 receptor type 1; IL-6, interleukin 6; ME, median eminence; NLP, neural lobe of the pituitary gland; OVLT, organum vasculosum of the lamina terminalis; PI, pineal gland; SCO, subcommissural organ; SFO, subfornical organ; TNF-ɑ, tumor necrosis factor alpha; TNFR, tumor necrosis factor receptor; VCAM1, vascular cell adhesion molecule 1

Fig. 3

Roadmap: Acute inflammatory events and Alzheimer’s disease To overcome prior barriers to progress in the immunity-AD field, longitudinal, multimodal appraisal of acute inflammatory events in diverse cohorts is needed. A proposed roadmap of studies needed to address gaps in the literature is depicted, focusing on biological, neuroimaging, and environmental assessments of the relationship between acute inflammatory exposures and long-term outcomes, as well as the development of interventional trials aimed at resolving systemic inflammation