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Review
. 2021 Aug 23;7(1):47-60.
doi: 10.3233/BPL-210127. eCollection 2021.

The Perfect Cytokine Storm: How Peripheral Immune Challenges Impact Brain Plasticity & Memory Function in Aging

Stephanie M Muscat  1   2 , Ruth M Barrientos  1   3   4   5
Affiliations
Review

The Perfect Cytokine Storm: How Peripheral Immune Challenges Impact Brain Plasticity & Memory Function in Aging

Stephanie M Muscat et al. Brain Plast. .

Abstract

Precipitous declines in cognitive function can occur in older individuals following a variety of peripheral immune insults, such as surgery, infection, injury, and unhealthy diet. Aging is associated with numerous changes to the immune system that shed some light on why this abrupt cognitive deterioration may occur. Normally, peripheral-to-brain immune signaling is tightly regulated and advantageous; communication between the two systems is bi-directional, via either humoral or neural routes. Following an immune challenge, production, secretion, and translocation of cytokines into the brain is critical to the development of adaptive sickness behaviors. However, aging is normally associated with neuroinflammatory priming, notably microglial sensitization. Microglia are the brain's innate immune cells and become sensitized with advanced age, such that upon immune stimulation they will mount more exaggerated neuroimmune responses. The resultant elevation of pro-inflammatory cytokine expression, namely IL-1β, has profound effects on synaptic plasticity and, consequentially, cognition. In this review, we (1) investigate the processes which lead to aberrantly elevated inflammatory cytokine expression in the aged brain and (2) examine the impact of the pro-inflammatory cytokine IL-1β on brain plasticity mechanisms, including its effects on BDNF, AMPA and NMDA receptor-mediated long-term potentiation.

Keywords: Biological aging; brain inflammation; cognitive decline; memory deficits; synaptic plasticity.

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Conflict of interest statement

The authors have no conflict of interest to report.

Figures

Fig. 1
Fig. 1
Peripheral immune challenges such as infection, surgery, and consumption of an unhealthy diet can evoke neuroinflammation, especially in the hippocampus. Such insults are known to activate the pattern recognition receptor TLR4, leading to activation of NF-κB and, ultimately, production of immature IL-1β (pro-IL-1β). Pro-IL-1β is cleaved by caspase-1, an inflammasome component, into mature IL-1β, which is released into the extracellular fluid. IL-1β elicits multiple effects on synaptic plasticity-related processes, including suppression of BDNF production, reduction of AMPAR membrane expression, and inhibition of LTP.
Fig. 2
Fig. 2
Optimal levels of IL-1 are needed for proper memory function. Inhibition of IL-1 signaling results in impaired synaptic plasticity. Likewise, exaggerated levels of IL-1 or hyperactivation of the IL-1 signaling pathway also impairs synaptic plasticity. Both aberrantly reduced and elevated IL-1 result in memory impairments. Thus, optimal levels of IL-1 are required for proper synaptic plasticity and hippocampal-dependent memory function.
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