Aging, sex, metabolic and life experience factors: Contributions to neuro-inflammaging in Alzheimer's disease research.

Alzheimer's disease (AD) is prevalent around the world, yet our understanding of the disease is still very limited. Recent work suggests that the cornerstone of AD may include the inflammation that accompanies it. Failure of a normal pro-inflammatory immune response to resolve may lead to persistent central inflammation that contributes to unsuccessful clearance of amyloid-beta plaques as they form, neuronal death, and ultimately cognitive decline. Individual metabolic, and dietary (lipid) profiles can differentially regulate this inflammatory process with aging, obesity, poor diet, early life stress and other inflammatory factors contributing to a greater risk of developing AD. Here, we integrate evidence for the interface between these factors, and how they contribute to a pro-inflammatory brain milieu. In particular, we discuss the importance of appropriate polyunsaturated fatty acids (PUFA) in the diet for the metabolism of specialised pro-resolving mediators (SPMs); raising the possibility for dietary strategies to improve AD outlook.

High-fat diet and aging-associated memory impairments persist in the absence of microglia in female rats.

Aging is associated with a priming of microglia such that they are hypersensitive to further immune challenges. As such high-fat diet during aging can have detrimental effects on cognition that is not seen in the young. However, conflicting findings also suggest that obesity may protect against cognitive decline during aging. Given this uncertainty we aimed here to examine the role of microglia in high-fat, high-sucrose diet (HFSD)-induced changes in cognitive performance in the aging brain. We hypothesised that 8 weeks of HFSD-feeding would alter microglia and the inflammatory milieu in aging and worsen aging-related cognitive deficits in a microglia-dependent manner. We found that both aging and HFSD reduced hippocampal neuron numbers and open field exploration; they also impaired recognition memory. However, the aging-related deficits occurred in the absence of a pro-inflammatory response and the deficits in memory performance persisted after depletion of microglia in the Cx3cr1-Dtr knock-in rat. Our data suggest that mechanisms additional to the acute microglial contribution play a role in aging- and HFSD-associated memory dysfunction.

The role of microglia and monocytes in the generation and resolution of the immune response in female and male rats.

Microglia have long been thought to be responsible for the initiation of the central nervous system (CNS) immune response to pathogen exposure. However, we recently reported that depleting CNS microglia and circulating monocytes does not abrogate the sickness response in male rats or mice to bacterial endotoxin, lipopolysaccharide (LPS). How the central immune response to an endotoxin challenge is initiated and resolved in the absence of microglia and monocytes remains unclear. Here we investigated the role of microglia and monocytes in driving the behavioral, febrile and neuroimmune response to LPS using the Cx3cr1-Dtr rat model of conditional microglia/monocyte depletion, assessed if this role is similar in females and males, and examined how the response to an immune challenge might be initiated in the absence of these cells. We show that depletion of microglia and monocytes exacerbates the response to LPS at each phase of the immune cascade. Our data indicate that the changes in the central response to immune challenge may be an indirect effect of excess neutrophil expansion into the bloodstream and infiltration into peripheral organs stimulating a rapid and exacerbated cytokine and prostaglandin response to the LPS that is not curtailed by the usual negative feedback mechanisms. Thus, we show that a demonstrable immune response can be generated (and resolved) in the near complete absence of microglia and monocytes and that these cells play a regulatory role in the initiation and resolution of the response to an immune challenge, rather than being critical for it to occur.