Neuroinflammatory challenges compromise neuronal function in the aging brain: Postoperative cognitive delirium and Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease that targets memory and cognition, and is the most common form of dementia among the elderly. Although AD itself has been extensively studied, very little is known about early-stage preclinical events and/or mechanisms that may underlie AD pathogenesis. Since the majority of AD cases are sporadic in nature, advancing age remains the greatest known risk factor for AD. However, additional environmental and epigenetic factors are thought to accompany increasing age to play a significant role in the pathogenesis of AD. Postoperative cognitive delirium (POD) is a behavioral syndrome that primarily occurs in elderly patients following a surgical procedure or injury and is characterized by disruptions in cognition. Individuals that experience POD are at an increased risk for developing dementia and AD compared to normal aging individuals. One way in which cognitive function is affected in cases of POD is through activation of the inflammatory cascade following surgery or injury. There is compelling evidence that immune challenges (surgery and/or injury) associated with POD trigger the release of pro-inflammatory cytokines into both the periphery and central nervous system. Thus, it is possible that cognitive impairments following an inflammatory episode may lead to more severe forms of dementia and AD pathogenesis. Here we will discuss the inflammation associated with POD, and highlight the advantages of using POD as a model to study inflammation-evoked cognitive impairment. We will explore the possibility that advancing age and immune challenges may provide mechanistic evidence correlating early life POD with AD. We will review and propose neural mechanisms by which cognitive impairments occur in cases of POD, and discuss how POD may augment the onset of AD.

Keywords: Aging; Alzheimer’s disease; BDNF; Neuroinflammation; Postoperative cognitive delirium.

Fig. 1

The Inflammatory Response in Young and Aged Brain. (A) Microglia in the young brain are in a resting state. Following an immune challenge (surgical procedure, medical condition, and/or infection) resting microglia become primed and then activated. Once activated, microglia synthesize and release the pro-inflammatory cytokine IL 1β which may target neuronal synapses in brain regions necessary for cognitive function. (B) Microglia in the aged brain differ from young in that they are in a basal primed state. Once activated, microglia produce an exaggerated inflammatory response characterized by significantly heightened levels of IL 1β that may persist for longer periods of time. The effects of an exaggerated inflammatory response in the old brain may lead to more robust declines in cognition and increase the risk for AD.