ReviewNeuroinflammation in the normal aging hippocampus
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
References (226)
- et al.
Central inhibition of interleukin-1beta ameliorates sickness behavior in aged mice
Brain Behav Immun
(2009) - et al.
Aging sensitizes mice to behavioral deficits induced by central HIV-1 gp120
Neurobiol Aging
(2008) - et al.
Fractalkine and CX 3 CR1 regulate hippocampal neurogenesis in adult and aged rats
Neurobiol Aging
(2011) - et al.
Receptors for interleukin-1 (alpha and beta) in mouse brain: mapping and neuronal localization in hippocampus
Neuroscience
(1991) - et al.
Adsorptive endocytosis of HIV-1gp120 by blood–brain barrier is enhanced by lipopolysaccharide
Exp Neurol
(1999) Voluntary exercise as an anti-neuroinflammatory therapeutic
Brain Behav Immun
(2011)- et al.
Memory for context is impaired by a post context exposure injection of interleukin-1 beta into dorsal hippocampus
Behav Brain Res
(2002) - et al.
Memory for context is impaired by injecting anisomycin into dorsal hippocampus following context exploration
Behav Brain Res
(2002) - et al.
Brain-derived neurotrophic factor mRNA downregulation produced by social isolation is blocked by intrahippocampal interleukin-1 receptor antagonist
Neuroscience
(2003) - et al.
BDNF mRNA expression in rat hippocampus following contextual learning is blocked by intrahippocampal IL-1beta administration
J Neuroimmunol
(2004)
Peripheral infection and aging interact to impair hippocampal memory consolidation
Neurobiol Aging
Time course of hippocampal IL-1 beta and memory consolidation impairments in aging rats following peripheral infection
Brain Behav Immun
Characterization of the sickness response in young and aging rats following E. coli infection
Brain Behav Immun
The role of hepatic and splenic macrophages in E. coli-induced memory impairments in aged rats
Brain Behav Immun
Greater glucocorticoid receptor activation in hippocampus of aged rats sensitizes microglia
Neurobiol Aging
Interleukin-1 Beta inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus
Brain Res
Alpha-tocopherol and selenium facilitate recovery from lipopolysaccharide-induced sickness in aged mice
J Nutr
Early-life infection leads to altered BDNF and IL-1beta mRNA expression in rat hippocampus following learning in adulthood
Brain Behav Immun
Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice
Psychoneuroendocrinology
Glucocorticoids sensitize the innate immune system through regulation of the NLRP3 inflammasome
J Biol Chem
Central nervous system injury triggers hepatic CC and CXC chemokine expression that is associated with leukocyte mobilization and recruitment to both the central nervous system and the liver
Am J Pathol
Overexpression of IL-1beta by adenoviral-mediated gene transfer in the rat brain causes a prolonged hepatic chemokine response, axonal injury and the suppression of spontaneous behaviour
Neurobiol Dis
Postoperative cognitive deficits and neuroinflammation in the hippocampus triggered by surgical trauma are exacerbated in aged rats
Prog Neuropsychopharmacol Biol Psychiatry
Aging and infection reduce expression of specific brain-derived neurotrophic factor mRNAs in hippocampus
Neurobiol Aging
Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system
Brain Behav Immun
The P38 mitogen-activated protein kinase inhibitor SB203580 antagonizes the inhibitory effects of interleukin-1beta on long-term potentiation in the rat dentate gyrus in vitro
Neuroscience
Exercise: a behavioral intervention to enhance brain health and plasticity
Trends Neurosci
Interleukin-1 (IL-1) and tumor necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro
Neurosci Lett
A role for c-Jun N-terminal kinase in the inhibition of long-term potentiation by interleukin-1beta and long-term depression in the rat dentate gyrus in vitro
Neuroscience
Glutamate uptake
Prog Neurobiol
Upregulation of nerve growth factor following cortical trauma
Exp Neurol
Stress is critical for LPS-induced activation of microglia and damage in the rat hippocampus
Neurobiol Aging
MRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging
Neurobiol Aging
IL-1RA blocks E. coli-induced suppression of Arc and long-term memory in aged F344xBN F1 rats
Brain Behav Immun
Aging sensitizes rapidly isolated hippocampal microglia to LPS ex vivo
J Neuroimmunol
Prior exposure to glucocorticoids sensitizes the neuroinflammatory and peripheral inflammatory responses to E. coli lipopolysaccharide
Brain Behav Immun
IL-1RA injected intra-cisterna magna confers extended prophylaxis against lipopolysaccharide-induced neuroinflammatory and sickness responses
J Neuroimmunol
Chronic exposure to exogenous glucocorticoids primes microglia to pro-inflammatory stimuli and induces NLRP3 mRNA in the hippocampus
Psychoneuroendocrinology
Physical exercise neuroprotects ovariectomized 3xTg-AD mice through BDNF mechanisms
Psychoneuroendocrinology
Voluntary wheel running, but not a diet containing (−)-epigallocatechin-3-gallate and beta-alanine, improves learning, memory and hippocampal neurogenesis in aged mice
Behav Brain Res
Spatial learning impairment in mice infected with Legionella pneumophila or administered exogenous interleukin-1-beta
Brain Behav Immun
Alpha-tocopherol reduces lipopolysaccharide-induced peroxide radical formation and interleukin-6 secretion in primary murine microglia and in brain
J Neuroimmunol
Vagal paraganglia bind biotinylated interleukin-1 receptor antagonist: a possible mechanism for immune-to-brain communication
Brain Res Bull
Pharmacokinetics, safety and immunomodulatory effects of human recombinant interleukin-1 receptor antagonist in healthy humans
Cytokine
Toll-like receptor (TLR) and inflammasome actions in the central nervous system
Trends Immunol
Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer’s disease
Brain Res
Peripheral administration of novel anti-inflammatories can attenuate the effects of chronic inflammation within the CNS
Brain Res
Chronic brain inflammation results in cell loss in the entorhinal cortex and impaired LTP in perforant path-granule cell synapses
Exp Neurol
Sustained hippocampal IL-1beta overexpression impairs contextual and spatial memory in transgenic mice
Brain Behav Immun
Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines
Brain Behav Immun
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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.