Elsevier

Neuroscience

Volume 309, 19 November 2015, Pages 84-99
Neuroscience

Review
Neuroinflammation in the normal aging hippocampus

https://doi.org/10.1016/j.neuroscience.2015.03.007Get rights and content

Highlights

  • Following challenge, the normal aged neuroinflammatory response is potentiated.

  • Sensitized microglia appears to be the source of this amplified response.

  • Elevated glucocorticoids may play a role in sensitizing microglia.

  • Potentiated neuroinflammation in the hippocampus leads to memory impairments.

  • Anti-inflammatory (e.g., exercise) interventions are effective treatments.

Abstract

A consequence of normal aging is a greater susceptibility to memory impairments following an immune challenge such as infection, surgery, or traumatic brain injury. The neuroinflammatory response, produced by these challenges results in increased and prolonged production of pro-inflammatory cytokines in the otherwise healthy aged brain. Here we discuss the mechanisms by which long-lasting elevations in pro-inflammatory cytokines in the hippocampus produce memory impairments. Sensitized microglia are a primary source of this exaggerated neuroinflammatory response and appear to be a hallmark of the normal aging brain. We review the current understanding of the causes and effects of normal aging-induced microglial sensitization, including dysregulations of the neuroendocrine system, potentiation of neuroinflammatory responses following an immune challenge, and the impairment of memories. We end with a discussion of therapeutic approaches to prevent these deleterious effects.

Introduction

It has long been noted in the clinical literature that otherwise healthy aging individuals often suffer precipitous declines in cognitive abilities, including long-term memory function, following an inflammatory challenge such as an infection (Anttila, 1992, Craft et al., 2012), a surgery (Bedford, 1955, Ramaiah and Lam, 2009), or a head injury (McAllister, 1992, Tokutomi et al., 2008, Senathi-Raja et al., 2010). Importantly, these mild cognitive impairments have been shown to increase susceptibility to the development of dementia later in life (Alzheimer’s Association, 2014). Notably, advanced age is the highest risk factor for suffering these mild cognitive impairments, as well as for developing dementia (Moller et al., 1998, Alzheimer’s Association, 2014). With the first of the baby boomer generation now turning 65, by the year 2030, approximately 23% of the U.S. population will be over 65 (Wimo et al., 2013, Alzheimer’s Association, 2014), a demographic phenomenon that has earned the term “silver tsunami” to characterize its magnitude. Because our unique memories are what make us individuals and give our lives meaning, insults that threaten to destroy already stored memories or disrupt our ability to form new memories can have devastating consequences. Caring for people with dementia in the U.S. has been projected to cost $20 trillion over the next 40 years (Alzheimer’s Association, 2014). Thus, in addition to the tremendous human suffering, the economic strain on the health care system and the federal budget is enormous. Therefore, scientific advances in the area of aging-related cognitive declines are of great and immediate importance. In this article, we will review the current literature related to hippocampal-dependent memory in normal aging and how it is negatively impacted by an inflammatory challenge. An important issue that merits attention here is the distinction between “normal” brain aging and “pathological” brain aging. Our work, as well as the preponderance of studies reviewed here, focuses on studying normal aging in which obvious neurodegeneration and senescence is not a prominent feature. Instead, older animals exhibit primed neuroinflammatory responses that require a secondary challenge for overt neuroinflammation or memory impairments to occur. A considerable amount of literature has also studied senescent animals, which exhibit basal behavioral and brain cytokine profiles dramatically different from those of younger animals, and whose brains are generally classified under the heading of “neurodegeneration” (Cacabelos et al., 1994, Luterman et al., 2000, Remarque et al., 2001). Neurodegeneration and the memory changes that depend on neurodegeneration are outside the scope of this review.

Section snippets

Communication between the peripheral immune system and the brain

Before considering the literature concerning immune challenge-induced hippocampal memory impairments, it is critical to understand that there is extensive bi-directional communication between the immune system and the central nervous system. Infection or injury initiates a peripheral acute phase response that involves a cascade of local and systemic events. Interleukin-1 beta (IL-1β), a pro-inflammatory cytokine, is a principal player in this cascade. As part of its role in this response, IL-1β

Microglial phenotype in normal aging: a shift toward an immunologically primed state

Microglia, as part of the myelomonocytic lineage, constitute the predominant innate immune cell in the brain and serve many functions including immunosurveillance of the brain microenvironment for pathogen invasion, danger signals, cellular debris, apoptotic cells, and alterations in neuronal phenotype (Kreutzberg, 1996). In the young adult brain, normally quiescent microglia become activated in response to a threat (Colton, 2009). Activated microglia undergo morphological changes, proliferate,

Aging-related potentiation of the neuroinflammatory response to challenge

Significantly elevated levels of pro-inflammatory cytokines such as IL-1β, in key brain regions responsible for mediating memory such as the hippocampus, have been shown to impair memory in young adult rats (Gibertini et al., 1995, Hauss-Wegrzyniak et al., 1998, Hauss-Wegrzyniak et al., 1999, Hauss-Wegrzyniak et al., 2002, Pugh et al., 1998, Pugh et al., 1999, Akana et al., 1999, Barrientos et al., 2002a, Barrientos et al., 2003, Barrientos et al., 2004, Hein et al., 2010, Jurgens et al., 2012

Effects of potentiated neuroinflammatory responses on hippocampal memory

The age-related exaggerated neuroinflammatory response to peripheral challenges such as a bacterial infection, surgery, or head trauma does not occur without significant costs to cognitive functions. For the purpose of this special issue review, which focuses on hippocampal vulnerability, we will limit the scope of this section to hippocampal memory. The hippocampus is critical for contextual and spatial learning and awareness, navigation, and episodic memories (Morris et al., 1982, Rudy et

Mechanisms of pro-inflammatory cytokine-induced hippocampal memory impairments

As discussed in previous sections, pro-inflammatory cytokines such as IL-1β, when elevated above basal levels in the hippocampus, impair hippocampal-dependent memory. How? Many mechanisms have been implicated in the actions of IL-1β on learning and memory processes. Below, we review several of these.

Elevations in hippocampal IL-1β have been shown to completely block long-term potentiation (LTP) in the hippocampus in vitro and in vivo (Katsuki et al., 1990, Bellinger et al., 1993, Cunningham et

Causes of microglial priming

Understanding the mechanism(s) that sensitize microglia during normal brain aging is of considerable importance in the context of developing effective treatments to attenuate neuroinflammatory-induced cognitive impairments. Several lines of research have recently emerged to shed some light on this issue. The first of these lines implicates various proteins that activate anti-inflammatory signals following ligand receptor interactions (Griffiths et al., 2009). We will focus on two such proteins

Therapeutic interventions

The evidence reviewed indicates that normal aging potentiates neuroinflammatory responses to immune challenges. The majority of studies have shown that an immune challenge in aged animals induced exaggerated brain cytokine responses causing impairments in long-term memory. Here we will discuss various studies demonstrating that pharmacological, dietary, and exercise-induced modulation of cytokines, or microglial phenotype, prior to an immune challenge blocks the behavioral effects of such

Summary

Taken together, the literature suggests that challenges such as a bacterial infection, surgery, or head injury produce neuroinflammatory responses that are exaggerated in the otherwise healthy aged brain. These exaggerated responses appear to be most prominent in the hippocampal formation, the critical brain region mediating contextual and spatial memory, and may be the cause of hippocampal memory impairments in aged individuals. The primary source of this neuroinflammatory response appears to

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    This work was supported by a grant from the National Institute on Aging R01AG028271 to R.M.B., L.R.W., & S.F.M.

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