The Impact of Systemic Inflammation on Alzheimer's Disease Pathology

Abstract

Alzheimer's disease (AD) is a devastating age-related neurodegenerative disorder with an alarming increasing prevalence. Except for the recently FDA-approved Aducanumab of which the therapeutic effect is not yet conclusively proven, only symptomatic medication that is effective for some AD patients is available. In order to be able to design more rational and effective treatments, our understanding of the mechanisms behind the pathogenesis and progression of AD urgently needs to be improved. Over the last years, it became increasingly clear that peripheral inflammation is one of the detrimental factors that can contribute to the disease. Here, we discuss the current understanding of how systemic and intestinal (referred to as the gut-brain axis) inflammatory processes may affect brain pathology, with a specific focus on AD. Moreover, we give a comprehensive overview of the different preclinical as well as clinical studies that link peripheral Inflammation to AD initiation and progression. Altogether, this review broadens our understanding of the mechanisms behind AD pathology and may help in the rational design of further research aiming to identify novel therapeutic targets.

Keywords: Alzheimer’s disease; gut-brain axis; neuroinflammation; peripheral inflammation; systemic inflammation.

Figure 1

Periphery-to-brain communication pathways. The periphery can communicate to the brain via neural and humoral routes. Peripheral organs project signals to varied cerebral regions via the vagus nerve (the neural route). Additionally, different humoral routes are used by the periphery to communicate to the brain: (1) Circulating immune mediators access the brain via the circumventricular organs (CVOs); (2) Peripheral immune cells cytokines and metabolites interact with their transporters on cerebral endothelial cells and choroid plexus epithelium (CPE) cells and subsequently enter to the brain; (3) Periphery-to-brain communication can occur via cell-mediated interactions between peripheral signals and brain cells which in turn lead to microglial activation and neuroinflammation. (4) Peripheral immune mediators activate choroid plexus epithelial cells and induces the release of extracellular vesicles (EVs). EVs enter the brain and can be engulfed by microglia to induce pro-inflammatory response. BBB, blood-brain barrier; CPE, choroid plexus epithelium; CVOs, circumventricular organs; CSF, cerebrospinal fluid; EVs, extracellular vesicles.

Figure 2

Cerebral changes in response to systemic inflammation. Systemic inflammation leads to increased levels of pro-inflammatory mediators. These signals can project to the brain via nerve afferents and the brain barriers. This can directly and/or indirectly induce neuronal cytotoxicity and affect Aβ transport resulting in increased Aβ aggregation. The aggregated Aβ induces an initial activation of microglial cells that leads to activated microglial cells with an impaired Aβ clearing ability. Additionally, the activated microglial cells produce a large amount of pro-inflammatory cytokines that further exacerbate neuroinflammation. This worsening of neuroinflammation promotes the development of brain pathology and ultimately leads to cognitive impairments.