Neuroinflammation as a Common Mechanism Associated with the Modifiable Risk Factors for Alzheimer's and Parkinson's Diseases.

BACKGROUND: Alzheimer's Disease (AD) and Parkinson's Disease (PD) are among the most common causes of dementia, which increasingly contribute to morbidity and mortality worldwide. A common hallmark in the pathogenesis of these two diseases is neuroinflammation, which is initially triggered by the presence of pathological structures associated with these disorders. Chronic neuroinflammation is sustained by persistent and aberrant microglial activation in the brain, which results in damage and death of neighboring cells, including neurons and glial cells. Two types of risk factors contribute to the development of AD and PD: non-modifiable risk factors and modifiable risk factors. Non-modifiable risk factors include genetic susceptibility that increases an individual's risk of developing the disease, whereas modifiable risk factors include a wide variety of health- and lifestyle-related factors that may be altered by changing individual behaviors. METHOD: Ovid Medline and PubMed databases were used to perform an ordered search of the peerreviewed research literature described in this review. RESULTS: This review focuses on four modifiable risk factors including physical inactivity, vascular disease-related conditions, obesity and type two diabetes mellitus, all of which have been identified as risk factors for the development of AD and PD. CONCLUSION: We highlight that control of the modifiable risk factors is a valid approach for managing the increased incidence of AD and PD. We describe neuroinflammatory mechanisms, which are common to AD and PD that may link both these neurodegenerative diseases with the four common modifiable risk factors. Understanding neuroinflammatory mechanisms could help identify novel therapeutic targets for combating these neurodegenerative diseases.

The effects of voluntary wheel running on neuroinflammatory status: Role of monocyte chemoattractant protein-1.

The health benefits of exercise and physical activity (PA) have been well researched and it is widely accepted that PA is crucial for maintaining health. One of the mechanisms by which exercise and PA exert their beneficial effects is through peripheral immune system adaptations. To date, very few studies have looked at the regulation of neuroimmune reactions in response to PA. We studied the effect of voluntary wheel running (VWR) on pro- and anti-inflammatory cytokine levels, patterns of glial cell activation and expression of immune receptors in the brains of female C57BL/6 mice. By using homozygous monocyte chemoattractant protein (MCP)-1 null mice, we investigated the role of this key immunoregulatory cytokine in mediating VWR-induced neuroinflammatory responses. We demonstrated that, compared to their sedentary counterparts, C57BL/6 mice exposed for seven weeks to VWR had increased levels of pro- and anti-inflammatory cytokines, markers of glial cell activation and a trend towards increased expression of toll-like receptor (TLR) 4 in the brain. Measurements of serum cytokines revealed that the alterations in brain cytokine levels could not be explained by the effects of PA on peripheral cytokine levels. We propose that the modified neuroimmune status observed in the VWR group represents an activated immune system, as opposed to a less activated immune system in the sedentary group. Since MCP-1 knockout mice displayed differing patterns of pro- and anti-inflammatory brain cytokine expression and glial activation when compared to their wild-type counterparts, we concluded that the effects of VWR on neuroimmune reactions may be modulated by MCP-1. These identified immunomodulatory effects of PA in the brain could contribute to the observed positive relationship between physically active lifestyles and a reduced risk for a number of neurodegenerative diseases that possess a significant neuroinflammatory component.

Insulin Modulates In Vitro Secretion of Cytokines and Cytotoxins by Human Glial Cells.

Alzheimer's disease (AD) is the most common form of dementia worldwide. Type 2 diabetes (T2D) has been implicated as a risk factor for AD. Since T2D is a peripheral inflammatory condition, and AD brains exhibit exacerbated neuroinflammation, we hypothesized that inflammatory mechanisms could contribute to the observed link between T2D and AD. Abnormal peripheral and brain insulin concentrations have been reported in both T2D and AD. The neurotrophic role of insulin has been described; however, this hormone can also regulate inflammatory responses in the periphery. Therefore we used in vitro human cell culture systems to elucidate the possible effects of insulin on neuroinflammation. We show that human astrocytes and microglia express both isoforms of the insulin receptor as well as the insulin-like growth factor (IGF)-1 receptor. They also express insulin receptor substrate (IRS)-1 and IRS-2, which are required for propagation of insulin/IGF- 1 signaling. We show that at low nanomolar concentrations, insulin could be pro-inflammatory by upregulating secretion of interleukin (IL)-6 and IL-8 from stimulated human astrocytes and secretion of IL-8 from stimulated human microglia. This effect dissipates at higher insulin concentrations. In contrast, insulin at a broader concentration range (10 pM - 1 µM) reduces the toxicity of stimulated human microglia and THP-1 monocytic cells towards SH-SY5Y neuronal cells. These data show that insulin may regulate the inflammatory status of glial cells by modulating their select functions, which in turn can influence the survival of neurons contributing to the observed link between T2D and AD.

Inflammation and insulin/IGF-1 resistance as the possible link between obesity and neurodegeneration.

Obesity is a growing epidemic that contributes to several brain disorders including Alzheimer's, Parkinson's, and Huntington's diseases. Obesity could promote these diseases through several different mechanisms. Here we review evidence supporting the involvement of two recently recognized factors linking obesity with neurodegeneration: the induction of pro-inflammatory cytokines and onset of insulin and insulin-like growth factor 1 (IGF-1) resistance. Excess peripheral pro-inflammatory mediators, some of which can cross the blood brain barrier, may trigger neuroinflammation, which subsequently exacerbates neurodegeneration. Insulin and IGF-1 resistance leads to weakening of neuroprotective signaling by these molecules and can contribute to onset of neurodegenerative diseases.