Aging-related changes in neuroimmune-endocrine function: implications for hippocampal-dependent cognition

Abstract

Healthy aged individuals are more likely to suffer profound memory impairments following a challenging life event such as a severe bacterial infection, surgery, or an intense psychological stressor, than are younger adults. Importantly, these peripheral challenges are capable of producing a neuroinflammatory response, (e.g., increased pro-inflammatory cytokines). In this review we will present the literature demonstrating that in the healthy aged brain this response is exaggerated and prolonged. Normal aging primes or sensitizes microglia and this appears to be the source of this amplified response. We will review the growing literature suggesting that a dysregulated neuroendocrine response in the aged organism is skewed toward higher brain CORT levels, and that this may play a critical role in priming microglia. Among the outcomes of an exaggerated neuroinflammatory response are impairments in synaptic plasticity, and reductions in key downstream mediators such as Arc and BDNF. We will show that each of these mechanisms is important for long-term memory formation, and is compromised by elevated pro-inflammatory cytokines.

Figure 1

Schematic depicting our working hypothesis. Upon a peripheral inflammatory, or stressor challenge in the young adult animal, once quiescent microglia are rapidly and transiently activated. Pro-inflammatory cytokines are released resulting in only moderate elevations above basal levels, and lasting no longer than 24 hours. Synaptic facilitation (LTP) and downstream mediators such as BDNF and Arc are moderately decreased resulting in mild to negligible memory impairments. In contrast, unchallenged aged microglia exhibit phenotypic markers of activation (i.e., MHCII), rendering them primed for a subsequent challenge. Upon a peripheral challenge, these microglia produce a sensitized neuroinflammatory response. Pro-inflammatory cytokine release is exaggerated and prolonged, lasting at least 8 days. Synaptic facilitation (LTP) and downstream mediators are profoundly reduced, and long-term contextual, and spatial memory is significantly impaired.

Figure 2

IL-1β protein levels in hippocampus of young and old rats following a peripheral vehicle or E. coli injection at 2 hours, 4 hours, 24 hours, 4 days, 8 days, and 14 days. Note that vehicle samples were collected at 3 hours and 24 hours and because they did not differ, were pooled to form just one vehicle control group for each age group. ^Significant difference between E. coli-treated and vehicle-treated groups. *Significant difference between age groups. Error bars indicate ± SEM. Modified with permission from Barrientos, et al., 2009.