Neuroinflammation in the normal aging hippocampus

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.

Keywords: danger signals; memory impairments; microglial priming; neuroendocrine dysregulation; neuroinflammation; normal aging.

Fig. 1

Schematic depiction of the current state of the literature. Upon being challenged with a bacterial or viral infection, a surgery, or a head injury, once quiescent microglia of the young adult animal are rapidly and transiently activated. Pro-inflammatory cytokines are released resulting in only modest elevations above basal levels, and lasting no longer than 24 h. Synaptic facilitation (LTP) and molecular mediators of long-term memory such as BDNF and Arc are also modestly decreased resulting in mild to negligible memory impairments. In contrast, aged microglia exhibit immunological and morphological markers of activation (i.e., MHCII, CD11b, CD86), rendering them primed for a subsequent challenge. Upon a challenge, these microglia produce a potentiated neuroinflammatory response. Pro-inflammatory cytokine release is exaggerated and prolonged, lasting at least 8 days. Synaptic facilitation (LTP) and molecular mediators of long-term memory are profoundly reduced, and long-term contextual, and spatial memory is significantly impaired.

Fig. 2

Therapeutic interventions. Pharmaceutical (e.g., IL-1RA, minocycline) interventions, exercise, and anti-oxidant rich diets have all been demonstrated to normalize the immunophenotype of the aged hippocampal microglia, thus reducing neuroinflammatory responses, and preventing long-term memory impairments.