Neuroinflammation as a mechanism linking hypertension with the increased risk of Alzheimer's disease.

Alzheimer's disease, the most common type of dementia among older adults, currently cannot be prevented or effectively treated. Only a very small percentage of Alzheimer's disease cases have an established genetic cause. The majority of Alzheimer's disease cases lack a clear causative event, but several modifiable factors have been associated with an increased risk of this disease. Persistent midlife hypertension is one such risk factor, which can be effectively controlled through changes in diet, lifestyle, and antihypertensive drugs. Identifying molecular mechanisms linking modifiable risk factors with the increased risk of Alzheimer's disease could enhance our understanding of this disease and lead to identification of novel targets and therapeutic approaches for effective treatments. Glial cell-driven neuroinflammation is one of the key pathological features of Alzheimer's disease. In this review, we illustrate that neuroinflammation could also be one of the possible mechanisms linking hypertension and Alzheimer's disease. Animal studies have demonstrated that chronically elevated blood pressure leads to adverse glial activation and increased brain inflammatory mediators. We highlight damage to cerebral microvasculature and locally activated renin-angiotensin system as the key pathogenetic mechanisms linking hypertension to neuroinflammation and the accompanying neurodegeneration. The role of tumor necrosis factor-α and interleukin-1ß as pro-inflammatory signaling molecules providing this link is discussed. We also summarize the available experimental data indicating that neuroinflammatory changes and glial activation can be reversed by several different classes of antihypertensive medicines. These studies suggest antihypertensives could be beneficial in Alzheimer's disease not only due to their ability to control the blood pressure, but also due to their anti-neuroinflammatory effects. Confirmation of these observations in human subjects is required and recent advances in the brain imaging techniques allowing visualization of both microglia and astrocyte activation will be essential for this research.

Resolution-Associated Molecular Patterns (RAMPs) as Endogenous Regulators of Glia Functions in Neuroinflammatory Disease.

Glial cells, including microglia and astrocytes, facilitate the survival and health of all cells within the Central Nervous System (CNS) by secreting a range of growth factors and contributing to tissue and synaptic remodeling. Microglia and astrocytes can also secrete cytotoxins in response to specific stimuli, such as exogenous Pathogen-Associated Molecular Patterns (PAMPs), or endogenous Damage-Associated Molecular Patterns (DAMPs). Excessive cytotoxic secretions can induce the death of neurons and contribute to the progression of neurodegenerative disorders, such as Alzheimer's disease (AD). The transition between various activation states of glia, which include beneficial and detrimental modes, is regulated by endogenous molecules that include DAMPs, cytokines, neurotransmitters, and bioactive lipids, as well as a diverse group of mediators sometimes collectively referred to as Resolution-Associated Molecular Patterns (RAMPs). RAMPs are released by damaged or dying CNS cells into the extracellular space where they can induce signals in autocrine and paracrine fashions by interacting with glial cell receptors. While the complete range of their effects on glia has not been described yet, it is believed that their overall function is to inhibit adverse CNS inflammatory responses, facilitate tissue remodeling and cellular debris removal. This article summarizes the available evidence implicating the following RAMPs in CNS physiological processes and neurodegenerative diseases: cardiolipin (CL), prothymosin α (ProTα), binding immunoglobulin protein (BiP), heat shock protein (HSP) 10, HSP 27, and αB-crystallin. Studies on the molecular mechanisms engaged by RAMPs could identify novel glial targets for development of therapeutic agents that effectively slow down neuroinflammatory disorders including AD.

Cytochrome c can be released into extracellular space and modulate functions of human astrocytes in a toll-like receptor 4-dependent manner.

BACKGROUND: Chronic activation of glial cells contributes to neurodegenerative diseases. Cytochrome c (CytC) is a soluble mitochondrial protein that can act as a damage-associated molecular pattern (DAMP) when released into the extracellular space from damaged cells. CytC causes immune activation of microglia in a toll-like receptor (TLR) 4-dependent manner. The effects of extracellular CytC on astrocytes are unknown. Astrocytes, which are the most abundant glial cell type in the brain, express TLR 4 and secrete inflammatory mediators; therefore, we hypothesized that extracellular CytC can interact with the TLR 4 of astrocytes inducing their release of inflammatory molecules and cytotoxins. METHOD: Experiments were conducted using primary human astrocytes, U118 MG human astrocytic cells, BV-2 murine microglia, and SH-SY5Y human neuronal cells. RESULTS: Extracellularly applied CytC increased the secretion of interleukin (IL)-1ß, granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-12 p70 by cultured primary human astrocytes. Anti-TLR 4 antibodies blocked the CytC-induced secretion of IL-1ß and GM-CSF by astrocytes. Supernatants from CytC-activated astrocytes were toxic to human SH-SY5Y neuronal cells. We also demonstrated CytC release from damaged glial cells by measuring CytC in the supernatants of BV-2 microglia after their exposure to cytotoxic concentrations of staurosporine, amyloid-ß peptides (Aß42) and tumor necrosis factor-α. CONCLUSION: CytC can be released into the extracellular space from damaged glial cells causing immune activation of astrocytes in a TLR 4-dependent manner. GENERAL SIGNIFICANCE: Astrocyte activation by CytC may contribute to neuroinflammation and neuronal death in neurodegenerative diseases. Astrocyte TLR 4 could be a potential therapeutic target in these diseases.

The Role of Mitochondrial Damage-Associated Molecular Patterns in Chronic Neuroinflammation.

Mitochondrial dysfunction has been established as a common feature of neurodegenerative disorders that contributes to disease pathology by causing impaired cellular energy production. Mitochondrial molecules released into the extracellular space following neuronal damage or death may also play a role in these diseases by acting as signaling molecules called damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs have been shown to initiate proinflammatory immune responses from nonneuronal glial cells, including microglia and astrocytes; thereby, they have the potential to contribute to the chronic neuroinflammation present in these disorders accelerating the degeneration of neurons. In this review, we highlight the mitochondrial DAMPs cytochrome c (CytC), mitochondrial transcription factor A (TFAM), and cardiolipin and explore their potential role in the central nervous system disorders including Alzheimer's disease and Parkinson's disease, which are characterized by neurodegeneration and chronic neuroinflammation.

Extracellular cytochrome c as an intercellular signaling molecule regulating microglial functions.

BACKGROUND: Cytochrome c is well known to be released from mitochondria into the cytosol where it can initiate apoptosis. Recent studies indicate that cytochrome c is also released into the extracellular space by both healthy and damaged cells, where its function is not well understood. We hypothesized that extracellular cytochrome c could function as an intercellular signaling molecule of the brain, which is recognized by brain microglia. These cells belong to the mononuclear phagocyte system and can be activated by endogenous substances associated with diverse pathologies including trauma, ischemic damage and neurodegenerative diseases. METHODS: Three different cell types were used to model microglia. Respiratory burst activity, nitric oxide production and cytotoxic secretions were measured following exposure of microglial cells to cytochrome c. RESULTS: We showed that extracellular cytochrome c primed the respiratory burst response of differentiated HL-60 cells, enhanced nitric oxide secretion by BV-2 cells, and augmented cytotoxicity of differentiated THP-1 cells. We demonstrated that the effects of cytochrome c on microglia-like cells were at least partially mediated by the toll-like receptor 4 (TLR4) and c-Jun N-terminal kinases (JNK) signaling pathway. CONCLUSIONS: Extracellular cytochrome c can interact with microglia TLR4 and modulate select functions of these brain immune cells. GENERAL SIGNIFICANCE: Our data identifies extracellular cytochrome c as a potential intercellular signaling molecule, which may be recognized by microglia causing or enhancing their immune activation. The data obtained support targeting TLR4 and JNK signaling as potential treatment strategies for brain diseases characterized by excessive cellular death and activation of microglia.

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.

Gold drug auranofin could reduce neuroinflammation by inhibiting microglia cytotoxic secretions and primed respiratory burst.

Neuroinflammation contributes to the pathogenesis of neurological disorders. Anti-inflammatory treatments could potentially be used to slow down the progression of these diseases. We studied the anti-neuroinflammatory activity of gold compounds which have been used to treat rheumatoid arthritis. Non-toxic concentrations of auranofin (0.1-1 µM) significantly reduced the cytotoxic secretions by primary human microglia and microglia-like THP-1 promonocytic cells. Auranofin inhibited primed NADPH-oxidase dependent respiratory burst and secretion of tumor necrosis factor (TNF)-α and nitric oxide by monocytic cells. It had a direct neuroprotective effect on SH-SY5Y neuronal cells. Auranofin could have a novel application in the treatment of neurodegenerative diseases.