Articles on Inflammation & Alzheimers 

McCoy MK. Tansey MG. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. [Review] [184 refs] Journal of Neuroinflammation. 5:45, 2008. The role of tumor necrosis factor (TNF) as an immune mediator has long been appreciated but its function in the brain is still unclear. TNF receptor 1 (TNFR1) is expressed in most cell types, and can be activated by binding of either soluble TNF (solTNF) or transmembrane TNF (tmTNF), with a preference for solTNF; whereas TNFR2 is expressed primarily by microglia and endothelial cells and is preferentially activated by tmTNF. Elevation of solTNF is a hallmark of acute and chronic neuroinflammation as well as a number of neurodegenerative conditions including ischemic stroke, Alzheimer's (AD), Parkinson's (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). The presence of this potent inflammatory factor at sites of injury implicates it as a mediator of neuronal damage and disease pathogenesis, making TNF an attractive target for therapeutic development to treat acute and chronic neurodegenerative conditions. However, new and old observations from animal models and clinical trials reviewed here suggest solTNF and tmTNF exert different functions under normal and pathological conditions in the CNS. A potential role for TNF in synaptic scaling and hippocampal neurogenesis demonstrated by recent studies suggest additional in-depth mechanistic studies are warranted to delineate the distinct functions of the two TNF ligands in different parts of the brain prior to large-scale development of anti-TNF therapies in the CNS. If inactivation of TNF-dependent inflammation in the brain is warranted by additional pre-clinical studies, selective targeting of TNFR1-mediated signaling while sparing TNFR2 activation may lessen adverse effects of anti-TNF therapies in the CNS.

Maczurek A. Hager K. Kenklies M. Sharman M. Martins R. Engel J. Carlson DA. Munch G. Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer's disease. [Review] [80 refs] Advanced Drug Delivery Reviews. 60(13-14):1463-70, 2008 Alzheimer's disease (AD) is a progressive neurodegenerative disorder that destroys patient memory and cognition, communication ability with the social environment and the ability to carry out daily activities. Despite extensive research into the pathogenesis of AD, a neuroprotective treatment - particularly for the early stages of disease - remains unavailable for clinical use. In this review, we advance the suggestion that lipoic acid (LA) may fulfil this therapeutic need. A naturally occurring cofactor for the mitochondrial enzymes pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, LA has been shown to have a variety of properties which can interfere with the pathogenesis or progression of AD. For example, LA increases acetylcholine (ACh) production by activation of choline acetyltransferase and increases glucose uptake, thus supplying more acetyl-CoA for the production of ACh. LA chelates redox-active transition metals, thus inhibiting the formation of hydroxyl radicals and also scavenges reactive oxygen species (ROS), thereby increasing the levels of reduced glutathione. In addition, LA down-regulates the expression of redox-sensitive pro-inflammatory proteins including TNF and inducible nitric oxide synthase. Furthermore, LA can scavenge lipid peroxidation products such as hydroxynonenal and acrolein. In human plasma, LA exists in an equilibrium of free and plasma protein bound form. Up to 150 muM, it is bound completely, most likely binding to high affinity fatty acid sites on human serum albumin, suggesting that one large dose rather than continuous low doses (as provided by "slow release" LA) will be beneficial for delivery of LA to the brain. Evidence for a clinical benefit for LA in dementia is yet limited. There are only two published studies, in which 600 mg LA was given daily to 43 patients with AD (receiving a standard treatment with choline-esterase inhibitors) in an open-label study over an observation period of up to 48 months. Whereas the improvement in patients with moderate dementia was not significant, the disease progressed extremely slowly (change in ADAScog: 1.2 points=year, MMSE: -0.6 points=year) in patients with mild dementia (ADAScog<15). Data from cell culture and animal models suggest that LA could be combined with nutraceuticals such as curcumin, (-)-epigallocatechin gallate (from green tea) and docosahexaenoic acid (from fish oil) to synergistically decrease oxidative stress, inflammation, Abeta levels and Abeta plaque load and thus provide a combined benefit in the treatment of AD. 

Infante-Duarte C. Waiczies S. Wuerfel J. Zipp F. New developments in understanding and treating neuroinflammation. [Review] [138 refs] Journal of Molecular Medicine. 86(9):975-85, 2008 We are currently witnesses to and authors of a paradigm shift in neuropathology. While classical acute and chronic neuroinflammatory diseases such as meningitis or multiple sclerosis (MS) present aspects of neurodegeneration, the disease course of progressive degenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), or stroke-mediated neuronal deficit are demonstrably affected by inflammation. These insights have immediate consequences both for research methods and for the development of novel, more efficient therapies for these diseases. In this review, we analyze the inflammatory and degenerative pathological mechanisms in the brain with particular emphasis on the classical chronic inflammatory disease MS. We demonstrate that the latest pathological considerations not only require the application of advanced research technologies to investigate new pathomechanistic pathways, but also affect the investigation, development, and monitoring of novel potential therapeutic tools. 

Vegeto E. Benedusi V. Maggi A. Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases. [Review] [267 refs] Frontiers in Neuroendocrinology. 29(4):507-19, 2008 Recent studies highlight the prominent role played by estrogens in protecting the central nervous system (CNS) against the noxious consequences of a chronic inflammatory reaction. The neurodegenerative process of several CNS diseases, including Multiple Sclerosis, Alzheimer's and Parkinson's Diseases, is associated with the activation of microglia cells, which drive the resident inflammatory response. Chronically stimulated during neurodegeneration, microglia cells are thought to provide detrimental effects on surrounding neurons. The inhibitory activity of estrogens on neuroinflammation and specifically on microglia might thus be considered as a beneficial therapeutic opportunity for delaying the onset or progression of neurodegenerative diseases; in addition, understanding the peculiar activity of this female hormone on inflammatory signalling pathways will possibly lead to the development of selected anti-inflammatory molecules. This review summarises the evidence for the involvement of microglia in neuroinflammation and the anti-inflammatory activity played by estrogens specifically in microglia.

Rogers J. The inflammatory response in Alzheimer's disease. [Review] [59 refs] Journal of Periodontology. 79(8 Suppl):1535-43, 2008 Over the last 2 decades, numerous innate inflammatory mediators have been reported to be upregulated in pathologically vulnerable regions of the brain in Alzheimer's disease (AD). These data have led to a reexamination of the dogma of brain immunologic privilege and to new studies that examine the role of the innate inflammatory response in a number of other neurologic disorders, particularly Parkinson's disease and human immunodeficiency virus dementia. In addition, basic science discoveries about neuroinflammation are now beginning to move to the clinic. More than 20 epidemiologic surveys have consistently demonstrated that common non-steroidal anti-inflammatory drugs may protect against the development of AD. By contrast, anti-inflammatory treatment trials for existing AD have typically shown little to no effect on halting or reversing the disorder, although the agents tested have often been at odds with those suggested by the epidemiologic and basic science results. The extensive literature on innate inflammation and neurologic disease notwithstanding, three fundamental questions still remain to be answered fully. First, are innate inflammatory responses a cause of neurologic disease or merely a more sophisticated means than previously imagined for removing the detritus left by more primary pathogenic mechanisms? Second, can anti-inflammatory agents effectively treat existing neurologic disease, or is a protective strategy in high-risk patients the only reasonable option? Third, whether for protection or treatment, what is the best choice of anti-inflammatory agent given the basic science mechanisms and epidemiologic results that have been reported? 

Kamer AR. Craig RG. Dasanayake AP. Brys M. Glodzik-Sobanska L. de Leon MJ. Inflammation and Alzheimer's disease: possible role of periodontal diseases. [Review] [50 refs] Alzheimer's & Dementia. 4(4):242-50, 2008 The molecular and cellular mechanisms responsible for the etiology and pathogenesis of Alzheimer's disease (AD) have not been defined; however, inflammation within the brain is thought to play a pivotal role. Studies suggest that peripheral infection/inflammation might affect the inflammatory state of the central nervous system. Chronic periodontitis is a prevalent peripheral infection that is associated with gram-negative anaerobic bacteria and the elevation of serum inflammatory markers including C-reactive protein. Recently, chronic periodontitis has been associated with several systemic diseases including AD. In this article we review the pathogenesis of chronic periodontitis and the role of inflammation in AD. In addition, we propose several potential mechanisms through which chronic periodontitis can possibly contribute to the clinical onset and progression of AD. Because chronic periodontitis is a treatable infection, it might be a readily modifiable risk factor for AD.

Vasto S. Candore G. Listi F. Balistreri CR. Colonna-Romano G. Malavolta M. Lio D. Nuzzo D. Mocchegiani E. Di Bona D. Caruso C. Inflammation, genes and zinc in Alzheimer's disease. [Review] [124 refs] Brain Research Reviews. 58(1):96-105, 2008 Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. AD has been linked to inflammation and metal biological pathway. Neuro-pathological hallmarks are senile plaques, resulting from the accumulation of several proteins and an inflammatory reaction around deposits of amyloid, a fibrillar protein, Abeta, product of cleavage of a much larger protein, the beta-amyloid precursor protein (APP) and neurofibrillary tangles. Amyloid deposition, due to the accumulation of Abeta peptide, is the main pathogenetic mechanism. Inflammation clearly occurs in pathologically vulnerable regions of AD and several inflammatory factors influencing AD development, i.e. environmental factors (pro-inflammatory phenotype) and/or genetic factors (pro-inflammatory genotype) have been described. At the biochemical level metals such as zinc are known to accelerate the aggregation of the amyloid peptide and play a role in the control of inflammatory responses. In particular, zinc availability may regulate mRNA cytokine expression, so influencing inflammatory network phenotypic expression.

Salinthone S. Yadav V. Bourdette DN. Carr DW. Lipoic acid: a novel therapeutic approach for multiple sclerosis and other chronic inflammatory diseases of the CNS. [Review] [143 refs] Endocrine, Metabolic & Immune Disorders Drug Targets. 8(2):132-42, 2008 The naturally occurring antioxidant lipoic acid (LA) was first described as an essential cofactor for the conversion of pyruvate to Acetyl-CoA, a critical step in respiration. LA is now recognized as a compound that has many biological functions. Along with its reduced form dihydrolipoic acid (DHLA), LA reduces and recycles cellular antioxidants such as glutathione, and chelates zinc, copper and other transition metal ions in addition to heavy metals. LA can also act as a scavenger of reactive oxygen and nitrogen species. By acting as an insulin mimetic agent, LA stimulates glucose uptake in many different cell types and can also modulate insulin signaling. The p38 and ERK MAP kinase pathways, AKT and NFkappaB are all regulated by LA. In addition, LA activates the prostaglandin EP2 and EP4 receptors to stimulate the production of the small molecule cyclic adenosine 5' monophosphate (cAMP). These diverse actions suggest that LA may be therapeutically effective in treating oxidative stress associated diseases. This review discusses the known biochemical properties of LA, its antioxidant properties, its ability to modulate signal transduction pathways, and the recent progress made in the utilization of LA as a therapeutic alternative for multiple sclerosis, Alzheimer's disease and diabetic neuropathy.

Hoozemans JJ. Rozemuller JM. van Haastert ES. Veerhuis R. Eikelenboom P. Cyclooxygenase-1 and -2 in the different stages of Alzheimer's disease pathology. [Review] [110 refs] Current Pharmaceutical Design. 14(14):1419-27, 2008. Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of beta amyloid (Abeta) protein and the formation of neurofibrillary tangles. In addition, there is an increase of inflammatory proteins in the brains of AD patients. Epidemiological studies, indicating that non-steroidal anti-inflammatory drugs (NSAIDs) decrease the risk of developing AD, have encouraged the study on the role of inflammation in AD. The best-characterized action of most NSAIDs is the inhibition of cyclooxygenase (COX). The expression of the constitutively expressed COX-1 and the inflammatory induced COX-2 has been intensively investigated in AD brain and different disease models for AD. Despite these studies, clinical trials with NSAIDs or selective COX-2 inhibitors showed little or no effect on clinical progression of AD. The expression levels of COX-1 and COX-2 change in the different stages of AD pathology. In an early stage, when low-fibrillar Abeta deposits are present and only very few neurofibrillary tangles are observed in the cortical areas, COX-2 is increased in neurons. The increased neuronal COX-2 expression parallels and colocalizes with the expression of cell cycle proteins. COX-1 is primarily expressed in microglia, which are associated with fibrillar Abeta deposits. This suggests that in AD brain COX-1 and COX-2 are involved in inflammatory and regenerating pathways respectively. In this review we will discuss the role of COX-1 and COX-2 in the different stages of AD pathology. Understanding the physiological and pathological role of cyclooxygenase in AD pathology may facilitate the design of therapeutics for the treatment or prevention of AD. 

Takeuchi M. Yamagishi S. Possible involvement of advanced glycation end-products (AGEs) in the pathogenesis of Alzheimer's disease. [Review] [71 refs] Current Pharmaceutical Design. 14(10):973-8, 2008 Alzheimer's disease (AD) is the most common cause of dementia in developed countries. AD is characterized pathologically by the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs), the major constituents of which are amyloid betaprotein and tau protein, respectively. Advanced glycation end-products (AGEs), senescent macroprotein derivatives formed at an accelerated rate under normal aging, can be identified immunohistochemically in both SPs and NFTs in AD patients. Further, recent clinical evidence has suggested diabetes mellitus as one of the risk factors for the development and progression of AD. Continuous hyperglycemia is a causative factor for diabetic vascular complications, and it enhances the generation of AGEs through the non-enzymatic glycation, thereby being involved in the pathogenesis of AD as well. Moreover, there is a growing body of evidence to show that the interaction of AGEs with a receptor for AGEs (RAGE) elicits reactive oxygen species generation and vascular inflammation, and subsequently alters various gene expressions in numerous types of cells, all of which could contribute to the pathological changes of diabetic vascular complications and AD. Indeed, we have recently found that glyceraldehyde-derived AGEs (Glycer-AGE) induce apoptotic cell death in cultured cortical neuronal cells. In addition, we also found that neurotoxic effect of diabetic serum on neuronal cells was blocked by neutralizing antibody raised against Glycer-AGE. In human AD brains, Glycer-AGE are actually detected in the cytosol of neurons in the hippocampus and para-hippocampal gyrus. These observations suggest that Glycer-AGE play a role in the pathogenesis of AD. In this review, we discuss the pathophysiological role for AGEs in the development and progression of AD, especially focusing on Glycer-AGE.

Marchalant Y. Brothers HM. Wenk GL. Inflammation and aging: can endocannabinoids help?. [Review] [75 refs] Biomedicine & Pharmacotherapy. 62(4):212-7, 2008 Aging often leads to cognitive decline due to neurodegenerative process in the brain. As people live longer, there exists a growing concern linked to long-term, slowly debilitating diseases, such as Alzheimer's disease for which a cure has not yet been found. Recently, the role of neuroinflammation has attracted attention due to its slow onset, chronic nature and its possible role in the development of many different neurodegenerative diseases. In the future, treatment of chronic neuroinflammation may help counteract aspects of neurodegenerative disease. Our recent studies have focused upon the endocannabinoid system for its unique effects on the expression of neuroinflammation. The basis for the manipulation of the endocannabinoid system in the brain in combination with existing treatments for Alzheimer's disease will be discussed in this review.

Wang K. Wan YJ. Nuclear receptors and inflammatory diseases. [Review] [148 refs] Experimental Biology & Medicine. 233(5):496-506, 2008 It is well known that the steroid hormone glucocorticoid and its nuclear receptor regulate the inflammatory process, a crucial component in the pathophysiological process related to human diseases that include atherosclerosis, obesity and type II diabetes, inflammatory bowel disease, Alzheimer's disease, multiple sclerosis, and liver tumors. Growing evidence demonstrates that orphan and adopted orphan nuclear receptors, such as peroxisome proliferator-activated receptors, liver x receptors, the farnesoid x receptor, NR4As, retinoid x receptors, and the pregnane x receptor, regulate the inflammatory and metabolic profiles in a ligand-dependent or -independent manner in human and animal models. This review summarizes the regulatory roles of these nuclear receptors in the inflammatory process and the underlying mechanisms. 

Erol A. An integrated and unifying hypothesis for the metabolic basis of sporadic Alzheimer's disease. [Review] [86 refs] Journal of Alzheimer's Disease. 13(3):241-53, 2008 Acquired disturbances of several aspects of cellular metabolism appear pathologically important in sporadic Alzheimer's disease (SAD). Among these, brain glucose utilization is reduced in the early stages of the disease. Hyperinsulinemia, which is a characteristic finding of insulin resistance, results in a central insulin deficit. Insufficient insulin signaling impairs the intricate balance of nitric oxide regulation of the central nervous system. Reduction in central insulin decreases neuronal nitric oxide synthase and increases inducible synthase activity. This, in turn, decreases astrocytic energy substrates and antioxidant supply of neurons. In addition, an increase in peroxynitrite formation impairs redox balance. Hyperleptinemia and glucose excess, which are the other parameters of insulin resistance, may worsen the reduced astrocytic energy supply and the ongoing inflammation via the inhibition of AMP-activated protein kinase (AMPK). Consequently, energy deficit and inflammation in neuronal tissue may cause neurodegeneration of SAD.

Chung JH. Seo AY. Chung SW. Kim MK. Leeuwenburgh C. Yu BP. Chung HY. Molecular mechanism of PPAR in the regulation of age-related inflammation. [Review] [102 refs] Ageing Research Reviews. 7(2):126-36, 2008 Evidence from many recent studies has linked uncontrolled inflammatory processes to aging and aging-related diseases. Decreased a nuclear receptor subfamily of transcription factors, peroxisome proliferator-activated receptors (PPARs) activity is closely associated with increased levels of inflammatory mediators during the aging process. The anti-inflammatory action of PPARs is substantiated by both in vitro and in vivo studies that signify the importance of PPARs as major players in the pathogenesis of many inflammatory diseases. In this review, we highlight the molecular mechanisms and roles of PPARalpha, gamma in regulation of age-related inflammation. By understanding these current findings of PPARs, we open up the possibility of developing new therapeutic agents that modulate these nuclear receptors to control various inflammatory diseases such as atherosclerosis, vascular diseases, Alzheimer's disease, and cancer. 

Conejero-Goldberg C. Davies P. Ulloa L. Alpha7 nicotinic acetylcholine receptor: a link between inflammation and neurodegeneration. [Review] [156 refs] Neuroscience & Biobehavioral Reviews. 32(4):693-706, 2008. Alzheimer's disease (AD) is the leading cause of dementia affecting over 25 million people worldwide. Classical studies focused on the description and characterization of the pathological hallmarks found in AD patients including the neurofibrillary tangles and the amyloid plaques. Current strategies focus on the etiology of these hallmarks and the different mechanisms contributing to neurodegeneration. Among them, recent studies reveal the close interplay between the immunological and the neurodegenerative processes. This article examines the implications of the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) as a critical link between inflammation and neurodegeneration in AD. Alpha7nAChRs are not only expressed in neurons but also in Glia cells where they can modulate the immunological responses contributing to AD. Successful therapeutic strategies against AD should consider the connections between inflammation and neurodegeneration. Among them, alpha7nAChR may represent a pharmacological target to control these two mechanisms during the pathogenesis of neurodegenerative and behavioral disorders. 

Eikelenboom P. Veerhuis R. Familian A. Hoozemans JJ. van Gool WA. Rozemuller AJ. Neuroinflammation in plaque and vascular beta-amyloid disorders: clinical and therapeutic implications. [Review] [10 refs] Neurodegenerative Diseases. 5(3-4):190-3, 2008. BACKGROUND: The cerebral beta-amyloid (Abeta) disorders show a great variability in the distribution of parenchymal and vascular amyloid deposits. OBJECTIVE: To study the relationship between amyloid deposition and inflammatory responses in three distinct subtypes of cerebral Abeta disorders. METHODS: The distribution of inflammatory proteins and cells in vascular and plaque amyloid deposits was evaluated in postmortem brain tissue using immunohistochemistry. The effects of a mixture of Abeta peptides and inflammation-related Abeta-associated proteins were studied in postmortem obtained human microglia cell cultures. RESULTS: The chronic inflammatory response is associated with amyloid plaques (but not with amyloid in the walls of larger vessels) in Alzheimer's disease (AD), with amyloid in cerebral arteries in hereditary cerebral hemorrhage with amyloidosis-Dutch type and with amyloid microangiopathy in the vascular variant of AD. Abeta(1-42) fibrils complexed with complement factor C1q and serum amyloid P component (the relevant amyloid-associated proteins) stimulate the production of proinflammatory cytokines in human microglia cell cultures and this production is attenuated by minocycline. CONCLUSION: The pattern of the chronic inflammatory response associated with fibrillar Abeta is strikingly different in the three studied types of Abeta disorders. The site of the fibrillar Abeta-induced chronic inflammatory response is closely related to clinical symptoms. Minocycline is a drug of interest to inhibit microglia-mediated neuroinflammatory response in Abeta brain disorders. 2008 S.

Karger AG, Basel Jofre-Monseny L. Minihane AM. Rimbach G. Impact of apoE genotype on oxidative stress, inflammation and disease risk. [Review] [107 refs] Molecular Nutrition & Food Research. 52(1):131-45, 2008 Although in developing countries an apolipoprotein E4 (apoE4) genotype may offer an evolutionary advantage, as it has been shown to offer protection against certain infectious disease, in Westernised societies it is associated with increased morbidity and mortality, and represents a significant risk factor for cardiovascular disease, late-onset Alzheimer's disease and other chronic disorders. ApoE is an important modulator of many stages of lipoprotein metabolism and traditionally the increased risk was attributed to higher lipid levels in E4 carriers. However, more recent evidence demonstrates the multifunctional nature of the apoE protein and the fact that the impact of genotype on disease risk may be in large part due to an impact on oxidative status or the immunomodulatory/anti-inflammatory properties of apoE. An increasing number of studies in cell lines, targeted replacement rodents and human volunteers indicate higher oxidative stress and a more pro-inflammatory state associated with the epsilon4 allele. The impact of genotype on the antioxidant and immunomodulatory/anti-inflammatory properties of apoE is the focus of the current review. Furthermore, current information on the impact of environment (diet, exercise, smoking status, alcohol) on apoE genotype-phenotype associations are discussed with a view to identifying particular lifestyle strategies that could be adapted to counteract the 'at-risk' E4 genotype. 

DeLegge MH. Smoke A. Neurodegeneration and inflammation. [Review] [54 refs] Nutrition in Clinical Practice. 23(1):35-41, 2008 Recent studies have demonstrated a strong link between neurodegeneration and chronic inflammation. The central nervous system (CNS) has very limited regenerative capacity. Neural cell death occurs by apoptosis and necrosis. Necrosis in the CNS usually follows ischemic or traumatic brain injury. Apoptosis is known as programmed cell death and often demonstrates histologic features of acute and chronic neurologic diseases. The innate immune response is protective to the CNS to defend against pathogens. Temporary up-regulation of inflammatory events is natural and does not lead to cell death. If this inflammatory process is up-regulated, neurodegenerative changes may occur. There has been a proven link between the inflammatory response, increased cytokine formation, and neurodegeneration. Both pharmaceutic and nutrition interventions for treating chronic neurodegenerative diseases, such as Alzheimer's disease or multiple sclerosis, will be focused on reducing or terminating the chronic inflammatory response. 

Vegeto E. Benedusi V. Maggi A. Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases. [Review] [267 refs] Frontiers in Neuroendocrinology. 29(4):507-19, 2008 Recent studies highlight the prominent role played by estrogens in protecting the central nervous system (CNS) against the noxious consequences of a chronic inflammatory reaction. The neurodegenerative process of several CNS diseases, including Multiple Sclerosis, Alzheimer's and Parkinson's Diseases, is associated with the activation of microglia cells, which drive the resident inflammatory response. Chronically stimulated during neurodegeneration, microglia cells are thought to provide detrimental effects on surrounding neurons. The inhibitory activity of estrogens on neuroinflammation and specifically on microglia might thus be considered as a beneficial therapeutic opportunity for delaying the onset or progression of neurodegenerative diseases; in addition, understanding the peculiar activity of this female hormone on inflammatory signalling pathways will possibly lead to the development of selected anti-inflammatory molecules. This review summarises the evidence for the involvement of microglia in neuroinflammation and the anti-inflammatory activity played by estrogens specifically in microglia. 

Marchalant Y. Brothers HM. Wenk GL. Inflammation and aging: can endocannabinoids help?. [Review] [75 refs] Biomedicine & Pharmacotherapy. 62(4):212-7, 2008 Aging often leads to cognitive decline due to neurodegenerative process in the brain. As people live longer, there exists a growing concern linked to long-term, slowly debilitating diseases, such as Alzheimer's disease for which a cure has not yet been found. Recently, the role of neuroinflammation has attracted attention due to its slow onset, chronic nature and its possible role in the development of many different neurodegenerative diseases. In the future, treatment of chronic neuroinflammation may help counteract aspects of neurodegenerative disease. Our recent studies have focused upon the endocannabinoid system for its unique effects on the expression of neuroinflammation. The basis for the manipulation of the endocannabinoid system in the brain in combination with existing treatments for Alzheimer's disease will be discussed in this review.

Rojo LE. Fernandez JA. Maccioni AA. Jimenez JM. Maccioni RB. Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer's disease. [Review] [185 refs] Archives of Medical Research. 39(1):1-16, 2008. During the past few years, an increasing set of evidence has supported the major role of deregulation of the interaction patterns between glial cells and neurons in the pathway toward neuronal degeneration. Neurons and glial cells, together with brain vessels, constitute an integrated system for brain function. Inflammation is a process related with the onset of several neurodegenerative disorders, including Alzheimer's disease (AD). Several hypotheses have been postulated to explain the pathogenesis of AD, but none provides insight into the early events that trigger metabolic and cellular alterations in neuronal degeneration. The amyloid hypothesis was sustained on the basis that Abeta-peptide deposition into senile plaques is responsible for neurodegeneration. However, recent findings point to Abeta oligomers as responsible for synaptic impairment in neuronal degeneration. Amyloid is only one among many other major factors affecting the quality of neuronal cells. Another explanation derives from the tau hypothesis, supported by the observations that tau hyperphosphorylations constitute a common feature of most of the altered signaling pathways in degenerating neurons. Altered tau patterns have been detected in the cerebrospinal fluids of AD patients, and a close correlation was observed between the levels of hyperphosphorylated tau isoforms and the degree of cognitive impairment. On the other hand, the anomalous effects of cytokines and trophic factors share in common the activation of tau hyperphosphorylation patterns. In this context, a neuroimmunological approach to AD becomes relevant. When glial cells that normally provide neurotrophic factors essential for neurogenesis are activated by a set of stressing events, they overproduce cytokines and NGF, thus triggering altered signaling patterns in the etiopathogenesis of AD. A solid set of discoveries has strengthened the idea that altered patterns in the glia-neuron interactions constitute early molecular events within the cascade of cellular signals that lead to neurodegeneration in AD. A direct correlation has been established between the Abeta-induced neurodegeneration and cytokine production and its subsequent release. In effect, neuroinflammation is responsible for an abnormal secretion of proinflammatory cytokines that trigger signaling pathways that activate brain tau hyperphosphorylation in residues that are not modified under normal physiological conditions. Other cytokines such as IL-3 and TNF-alpha seem to display neuroprotective activities. Elucidation of the events that control the transitions from neuroprotection to neurodegeneration should be a critical point toward elucidation of AD pathogenesis. 

Obregon D. Hou H. Bai Y. Nikolic WV. Mori T. Luo D. Zeng J. Ehrhart J. Fernandez F. Morgan D. Giunta B. Town T. Tan J. CD40L disruption enhances Abeta vaccine-mediated reduction of cerebral amyloidosis while minimizing cerebral amyloid angiopathy and inflammation. Neurobiology of Disease. 29(2):336-53, 2008. Amyloid-beta (Abeta) immunization efficiently reduces amyloid plaque load and memory impairment in transgenic mouse models of Alzheimer's disease (AD). Active Abeta immunization has also yielded favorable results in a subset of AD patients. However, a small percentage of patients developed severe aseptic meningoencephalitis associated with brain inflammation and infiltration of T-cells. We have shown that blocking the CD40-CD40 ligand (L) interaction mitigates Abeta-induced inflammatory responses and enhances Abeta clearance. Here, we utilized genetic and pharmacologic approaches to test whether CD40-CD40L blockade could enhance the efficacy of Abeta(1-42) immunization, while limiting potentially damaging inflammatory responses. We show that genetic or pharmacologic interruption of the CD40-CD40L interaction enhanced Abeta(1-42) immunization efficacy to reduce cerebral amyloidosis in the PSAPP and Tg2576 mouse models of AD. Potentially deleterious pro-inflammatory immune responses, cerebral amyloid angiopathy (CAA) and cerebral microhemorrhage were reduced or absent in these combined approaches. Pharmacologic blockade of CD40L decreased T-cell neurotoxicity to Abeta-producing neurons. Further reduction of cerebral amyloidosis in Abeta-immunized PSAPP mice completely deficient for CD40 occurred in the absence of Abeta immunoglobulin G (IgG) antibodies or efflux of Abeta from brain to blood, but was rather correlated with anti-inflammatory cytokine profiles and reduced plasma soluble CD40L. These results suggest CD40-CD40L blockade promotes anti-inflammatory cellular immune responses, likely resulting in promotion of microglial phagocytic activity and Abeta clearance without generation of neurotoxic Abeta-reactive T-cells. Thus, combined approaches of Abeta immunotherapy and CD40-CD40L blockade may provide for a safer and more effective Abeta vaccine. 

Guerreiro RJ. Santana I. Bras JM. Santiago B. Paiva A. Oliveira C. Peripheral inflammatory cytokines as biomarkers in Alzheimer's disease and mild cognitive impairment. Neurodegenerative Diseases. 4(6):406-12, 2007. BACKGROUND: Several lines of evidence in the literature have shown that inflammation is involved in the pathogenesis of Alzheimer's disease (AD). However, the results from the evaluation of serum inflammatory markers in AD patients have been controversial. OBJECTIVE: To determine if any differences exist in the monocytic secretion pattern of IL-1beta, IL-6, IL-12 and TNF-alpha from mild cognitive impairment (MCI) and AD patients, when compared with healthy age-matched controls. METHODS: To evaluate the percentage of peripheral monocytes secreting IL-1beta, IL-6, IL-12 and TNF-alpha along with the relative levels of these proteins, a cytofluorimetric analysis was conducted under basal conditions and after lipopolysaccharide-induced cell activation. RESULTS: We found, in AD and MCI patients, a significant raise in the percentage of monocytes producing the studied cytokines (under basal conditions and after the exposure to an inflammatory stimulus), as well as a decreased competence of these cells to respond to inflammatory challenges, when compared with controls. CONCLUSIONS: These results agree with a persistent inflammatory status in AD, reinforcing the hypothesis of a progressive impairment of the immune response in this disorder and suggesting that monocytes may be good targets to study the progression from MCI to AD. 

Rao AA. Sridhar GR. Das UN. Elevated butyrylcholinesterase and acetylcholinesterase may predict the development of type 2 diabetes mellitus and Alzheimer's disease. Medical Hypotheses. 69(6):1272-6, 2007. Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and lipid peroxides are elevated and concentrations of endothelial nitric oxide (eNO) decreased in type 2 diabetes mellitus and Alzheimer's disease. This suggests that both these diseases are low-grade systemic inflammatory conditions and are closely associated with each other. Recent studies revealed that plasma and tissue concentrations of enzymes butyrylcholinesterase and acetylcholinesterase are elevated in type 2 diabetes and Alzheimer's disease. Acetylcholine has anti-inflammatory actions. Hence, elevated butyrylcholinesterase and acetylcholinesterase concentrations will lead to a decrease in the levels of acetylcholine that could trigger the onset of low-grade systemic inflammation seen in type 2 diabetes and Alzheimer's disease. In view of this, we propose that butyrylcholinesterase and acetylcholinesterase will not only serve as therapeutic targets but also may serve as markers to predict the development of type 2 diabetes mellitus and Alzheimer's disease. 

Whitehead SN. Cheng G. Hachinski VC. Cechetto DF. Progressive increase in infarct size, neuroinflammation, and cognitive deficits in the presence of high levels of amyloid. Stroke. 38(12):3245-50, 2007 BACKGROUND AND PURPOSE: In the elderly, cerebral ischemia (CI) occurs in the presence of high levels of amyloid. Neuroinflammation plays a critical role in the pathophysiology of Alzheimer's disease and CI. This study examined infarct size, neuroinflammation, and cognitive deficits over time in rat models of Alzheimer's disease and CI. METHODS: beta-amyloid toxicity was modeled using bilateral intracerebroventricular injections of beta-amyloid 25 to 35 peptides. CI was modeled using unilateral injections of the potent vasoconstrictor, endothelin-1, into the striatum. RESULTS: Infarct volumes were higher in the presence of amyloid and compared with the CI model alone. In the CI model alone, the infarct volume was significantly smaller 28 days after surgery compared with 7 days after surgery. However, when Alzheimer's disease and CI models were combined, the infarct volume was significantly larger 28 days after surgery compared with 7 days after surgery. The neuroinflammation in the region of the infarct was also significantly increased. The Barnes circular platform test showed time-dependent increases in memory and learning deficits in the beta-amyloid-treated rats that were even greater when beta-amyloid treatment was combined with CI. CONCLUSIONS: CI in the presence of high levels of amyloid results in progressive increases in infarct size, neuroinflammation, and cognitive deficits. 

Zuliani G. Guerra G. Ranzini M. Rossi L. Munari MR. Zurlo A. Ble A. Volpato S. Atti AR. Fellin R. High interleukin-6 plasma levels are associated with functional impairment in older patients with vascular dementia. International Journal of Geriatric Psychiatry. 22(4):305-11, 2007. In older individuals, inflammatory mechanisms have been linked to the pathogenesis of both dementia and functional impairment. In this cross-sectional study we have investigated the possible association between some markers of systemic inflammation and functional status, in a sample of one hundred and forty older demented patients including 60 patients with late onset Alzheimer's disease (LOAD) and 80 with vascular dementia (VD). Functional status was evaluated by Barthel Index (BI); the total score ranged from 0 (total dependency) to 20 (total autonomy). Interleukin-1beta, Tumor Necrosis Factor-alpha, Interleukin- 6, Interleukin- 8, and Transforming Grow Factor beta were quantified by ELISA. Among the cytokines evaluated, only IL-6 was correlated with the BI (r: -0.32, p < 0.001). The mean levels of IL-6 progressively decreased from I (9.50 pg/mL), to II (6.40 pg/mL), to III BI tertile (4.80 pg/mL) (p < 0.02). At multiple regression analysis, IL-6 was associated with BI in the whole sample and in VD, but not in LOAD, independent of age, gender, smoking, alcohol consumption, hypertension, diabetes, coronary heart disease, previous stroke, and mini mental state examination score. Our study suggests the existence of an independent and negative relationship between IL-6 plasma levels and functional status in older individuals with vascular dementia. This finding might contribute to explain the 'excess of disability' phenomenon described in older demented patients. 

Jefferson AL. Massaro JM. Wolf PA. Seshadri S. Au R. Vasan RS. Larson MG. Meigs JB. Keaney JF Jr. Lipinska I. Kathiresan S. Benjamin EJ. DeCarli C. Inflammatory biomarkers are associated with total brain volume: the Framingham Heart Study. Neurology. 68(13):1032-8, 2007. BACKGROUND: Systemic inflammation is associated with ischemia and Alzheimer disease (AD). We hypothesized that inflammatory biomarkers would be associated with neuroimaging markers of ischemia (i.e., white matter hyperintensities [WMH]) and AD (i.e., total brain volume [TCB]). METHODS: MRI WMH and TCB were quantified on 1,926 Framingham Offspring participants free from clinical stroke, TIA, or dementia (mean age 60 +/- 9 years; range 35 to 85 years; 54% women) who underwent measurement of a circulating inflammatory marker panel, including CD40 ligand, C-reactive protein, interleukin-6 (IL-6), soluble intracellular adhesion molecule-1, monocyte chemoattractant protein-1, myeloperoxidase, osteoprotegerin (OPG), P-selectin, tumor necrosis factor-alpha (TNFalpha), and tumor necrosis factor receptor II. To account for head size, both TCB (TCBV) and WMH (WMH/TCV) were divided by total cranial volume. We used multivariable linear regression to relate 10 log-transformed inflammatory biomarkers to brain MRI measures. RESULTS: In multivariable models, inflammatory markers as a group were associated with TCBV (p < 0.0001) but not WMH/TCV (p = 0.28). In stepwise models adjusted for clinical covariates with backwards elimination of markers, IL-6 and OPG were inversely associated with TCBV; TNFalpha was inversely related to TCBV in a subset of 1,430 participants. Findings were similar in analyses excluding individuals with prevalent cardiovascular disease. The relations between TCBV and inflammatory markers were modified by both sex and age, and generally were more pronounced in men and in older individuals. CONCLUSIONS: Although our observational cross-sectional data cannot establish causality, they are consistent with the hypothesis that higher inflammatory markers are associated with greater atrophy than expected for age. 

Heneka MT. O'Banion MK. Inflammatory processes in Alzheimer's disease. [Review] [324 refs] Journal of Neuroimmunology. 184(1-2):69-91, 2007. Generation and deposition of amyloid beta peptides and neurofibrillary tangle formation are key mechanisms involved in AD pathogenesis. Recent evidence suggests that inflammatory mechanisms represent a third component which, once initiated by degeneration, may significantly contribute to disease progression and chronicity. Various neuroinflammatory mediators including complement activators and inhibitors, chemokines, cytokines, radical oxygen species and inflammatory enzymes are generated and released by microglia, astrocytes and neurons. Degeneration of aminergic brain stem nuclei such as the locus ceruleus and the nucleus baslis of Meynert may facilitate the occurrence of inflammation in their respective projection areas given the antiinflammatory and neuroprotective action of their key products norepinephrine and acetylcholine. While inflammation has been thought to arise secondary to degeneration, recent experiments demonstrated that inflammatory mediators may stimulate APP processing by upregulation of beta secretase 1 and therefore are able to establish a vicious cycle. Despite the fact that some aspects of inflammation may even exert protective effects to bystander neurons, antiinflammatory treatment strategies should therefore be considered. Non-steroidal antiinflammatory drugs have been shown to reduce the risk and delay the onset to develop AD. However, the precise molecular mechanism underlying this effect is still being debated. Several mechanisms including inhibition of cyclooxygenase 2, gamma secretase or activation of the peroxisome proliferator activated receptor gamma may alone or, more likely, in concert account for the epidemiologically observed protection. 

Leonard BE. Inflammation, depression and dementia: are they connected? [Review] [82 refs] Neurochemical Research. 32(10):1749-56, 2007. Chronic inflammation is now considered to be central to the pathogenesis not only of such medical disorders as cardiovascular disease, multiple sclerosis, diabetes and cancer but also of major depression. If chronic inflammatory changes are a common feature of depression, this could predispose depressed patients to neurodegenerative changes in later life. Indeed there is now clinical evidence that depression is a common antecedent of Alzheimer's disease and may be an early manifestation of dementia before the cognitive declines becomes apparent. This review summarises the evidence that links chronic low grade inflammation with changes in brain structure that could precipitate neurodegenerative changes associated with Alzheimer's disease and other dementias. For example, neuronal loss is a common feature of major depression and dementia. It is hypothesised that the progress from depression to dementia could result from the activation of macrophages in the blood, and microglia in the brain, that release pro-inflammatory cytokines. Such cytokines stimulate a cascade of inflammatory changes (such as an increase in prostaglandin E2, nitric oxide in addition to more pro-inflammatory cytokines) and a hypersecretion of cortisol. The latter steroid inhibits protein synthesis thereby reducing the synthesis of neurotrophic factors and preventing reairto damages neuronal networks. In addition, neurotoxic end products of the tryptophan-kynurenine pathway, such as quinolinic acid, accumulate in astrocytes and neurons in both depression and dementia. Thus increased neurodegeneration, reduced neuroprotection and neuronal repair are common pathological features of major depression and dementia. Such changes may help to explain why major depression is a frequent prelude to dementia in later life. 

von Bernhardi R. Glial cell dysregulation: a new perspective on Alzheimer disease. [Review] [190 refs] Neurotoxicity Research. 12(4):215-32, 2007. Alzheimer disease (AD) is a major cause of dementia. Several mechanisms have been postulated to explain its pathogenesis, beta-amyloid (A beta toxicity, cholinergic dysfunction, Tau hyper-phosphorylation, oxidative damage, synaptic dysfunction and inflammation secondary to senile plaques, among others. Glial cells are the major producers of inflammatory mediators, and cytotoxic activation of glial cells is linked to several neurodegenerative diseases; however, whether inflammation is a consequence or the cause of neurodegeneration is still unclear. I propose that inflammation and cellular stress associated with aging are key events in the development of AD through the induction of glial dysfunction. Dysregulated inflammatory response can elicit glial cell activation by compounds which are normally poorly reactive. Inflammation can also be the major cause of defective handling of A beta and the amyloid precursor protein (APP). Here I review evidence that support the proposal that dysfunctional glia and the resulting neuroinflammation can explain many features of AD. Evidence supports the notion that damage caused by inflammation is not only a primary cause of neurodegeneration but also an inducer for the accumulation of A beta in AD. Dysfunctional glia can result in impaired neuronal function in AD, as well as in many progressive neurodegenerative disorders. We show that microglial cell activation is enhanced under pro-inflammatory conditions, indicating that glial cell responses to A beta related proteins can be critically dependent on the priming of glial cells by pro-inflammatory factors. 

Watson GS. Craft S. Insulin resistance, inflammation, and cognition in Alzheimer's Disease: lessons for multiple sclerosis. [Review] [148 refs] Journal of the Neurological Sciences. 245(1-2):21-33, 2006. Insulin resistance (reduced ability of insulin to stimulate glucose utilization) is common in North American and Europe, where as many as one third of all older adults suffer from prodromal or clinical type 2 diabetes mellitus. It has long been known that insulin-resistant conditions adversely affect general health status. A growing body of findings suggests that insulin contributes to normal brain functioning and that peripheral insulin abnormalities increase the risk for memory loss and neurodegenerative disorders such as Alzheimer's disease. Potential mechanisms for these effects include insulin's role in cerebral glucose metabolism, peptide regulation, modulation of neurotransmitter levels, and modulation of many aspects of the inflammatory network. An intriguing question is whether insulin abnormalities also influence the pathophysiology of multiple sclerosis (MS), an autoimmune disorder characterized by elevated inflammatory biomarkers, central nervous system white matter lesions, axonal degeneration, and cognitive impairment. MS increases the risk for type 1 diabetes mellitus. Furthermore, the lack of association between MS and type 2 diabetes may suggest that insulin resistance affects patients with MS and the general population at the same alarming rate. Therefore, insulin resistance may exacerbate phenomena that are common to MS and insulin-resistant conditions, such as cognitive impairments and elevated inflammatory responses. Interestingly, the thiazolidinediones, which are used to treat patients with type 2 diabetes, have been proposed as potential therapeutic agents for both Alzheimer's disease and MS. The agents improve insulin sensitivity, reduce hyperinsulinemia, and exert anti-inflammatory actions. Ongoing studies will determine whether thiazolidinediones improve cognitive functioning for patients with type 2 diabetes or Alzheimer's disease. Future studies are needed to examine the effects of thiazolidinediones on patients with MS. 

Shishodia S. Sethi G. Aggarwal BB. Curcumin: getting back to the roots. Annals of the New York Academy of Sciences. 1056:206-17, 2005. The use of turmeric, derived from the root of the plant Curcuma longa, for treatment of different inflammatory diseases has been described in Ayurveda and in traditional Chinese medicine for thousands of years. The active component of turmeric responsible for this activity, curcumin, was identified almost two centuries ago. Modern science has revealed that curcumin mediates its effects by modulation of several important molecular targets, including transcription factors (e.g., NF-kappaB, AP-1, Egr-1, beta-catenin, and PPAR-gamma), enzymes (e.g., COX2, 5-LOX, iNOS, and hemeoxygenase-1), cell cycle proteins (e.g., cyclin D1 and p21), cytokines (e.g., TNF, IL-1, IL-6, and chemokines), receptors (e.g., EGFR and HER2), and cell surface adhesion molecules. Because it can modulate the expression of these targets, curcumin is now being used to treat cancer, arthritis, diabetes, Crohn's disease, cardiovascular diseases, osteoporosis, Alzheimer's disease, psoriasis, and other pathologies. Interestingly, 6-gingerol, a natural analog of curcumin derived from the root of ginger (Zingiber officinalis), exhibits a biologic activity profile similar to that of curcumin. The efficacy, pharmacologic safety, and cost effectiveness of curcuminoids prompt us to "get back to our roots." 

Townsend KP. Pratico D. Novel therapeutic opportunities for Alzheimer's disease: focus on nonsteroidal anti-inflammatory drugs. [Review] [88 refs] FASEB Journal. 19(12):1592-601, 2005. Alzheimer's disease (AD) is the most common form of neurodegenerative disorder with dementia in the elderly. The AD brain pathology is characterized by deposits of amyloid-beta (Abeta) peptides and neurofibrillary tangles but also (among other aspects) by signs of a chronic inflammatory process. Epidemiological studies have shown that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD and delays its onset. Classical targets of NSAIDs include cycloxygenase, nuclear factor kappaB, and peroxisome proliferator-activated receptors. Modulation of these pathways, all of which have been implicated in AD pathogenesis, could explain the NSAID effect on AD progression. However, recent studies indicate that a subset of NSAIDs such as ibuprofen, indomethacin, and flurbiprofen may have direct Abeta-lowering properties in cell cultures as well as transgenic models of AD-like amyloidosis. A renewed interest in the old and a discovery of new pharmacological properties of these drugs are providing vital insight for future clinical trials. In this review we will summarize how the combination of traditional (anti-inflammatory) and new (anti-amyloidogenic) properties of some NSAIDs is providing unprecedented opportunities for drug discovery and could potentially result in novel therapeutic approaches for the treatment of AD. 

Rozemuller AJ. van Gool WA. Eikelenboom P. The neuroinflammatory response in plaques and amyloid angiopathy in Alzheimer's disease: therapeutic implications. [Review] [140 refs] Current Drug Targets - Cns & Neurological Disorders. 4(3):223-33, 2005. The amyloid plaques in Alzheimer's disease (AD) brains are co-localised with a broad variety of inflammation-related proteins (complement proteins, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that the Abeta depositions in the neuroparenchyma are closely associated with a locally-induced, non-immune-mediated chronic inflammatory response. Clinicopathological and neuroradiological data show that activation of microglia are a relatively early pathogenic event that precedes the process of severe neuropil destruction in patients. Recent gene findings (cDNA microarray) confirm the immunohistochemical findings of an early involvement of inflammatory and regenerative pathways in AD pathogenesis. Abeta deposition, inflammation and regenerative mechanisms are also early pathogenic events in transgenic mice models harbouring the pathological AD mutations, while "later" neurodegenerative characteristics are not seen in these models. Next to the plaques, Abeta amyloid deposition is frequently found in the walls of cerebral vessels (cerebral amyloid angiopathy). Most common is the type of amyloid deposition in the walls of meningeal and medium-sized cortical arteries, and more rarely, microcapillary amyloid angiopathy (dyshoric angiopathy). Immunohistochemical studies show that in AD patients, the majority of the amyloid deposits in the walls of the larger vessels is not associated with a chronic inflammatory response in contrast to micro-capillary amyloid angiopathy. In this contribution, we will give an overview of the similarities and differences between the involvement of inflammatory mechanisms in vascular and plaque amyloid in AD and transgenic models. The implications of the reviewed studies for an inflammation-based therapeutical approach in AD will be discussed.   

Klegeris A. McGeer PL. Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents in the treatment of neurodegenerative disease. [Review] [192 refs] Current Alzheimer Research. 2(3):355-65, 2005. Inflammation is characteristic of a broad spectrum of neurodegenerative diseases. These include Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases, amyotrophic lateral sclerosis, all of the tauopathies, multiple sclerosis and many other less common conditions. Morphologically, the level of inflammation is determined by the concentration and degree of activation of microglial cells. Biochemically, it is judged by the presence of a spectrum of inflammatory mediators. Epidemiological evidence indicates that anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs) have a sparing effect on AD and PD indicating that inflammation exacerbates the pathology in these diseases. NSAIDs are protective in transgenic animal models of AD, providing further evidence of the negative consequences of inflammation. Here we describe an in vitro model, which was used to study the protective effects of NSAIDs in AD. This model is based on neuronal cell killing by stimulated microglia or microglia-like cells. In this model NSAIDs show protective effects at a therapeutically relevant level, which is in the low micromolar range. There are reports suggesting that NSAIDs act independently of cyclooxygenase (COX) inhibition, but only at higher doses. Classical NSAIDs are still the most logical choice for agents that will slow the progression or delay the onset of AD and other neurodegenerative diseases despite failures of naproxen, celecoxib and rofecoxib in AD clinical trials. Several other classes of anti-inflammatory drugs have been identified as potentially beneficial in this and similar assay systems. Therefore combination therapy with other anti-inflammatory agents that work through different mechanisms of action might prove to be a superior therapeutic strategy. 

Koistinaho M. Koistinaho J. Interactions between Alzheimer's disease and cerebral ischemia--focus on inflammation. [Review] [159 refs] Brain Research - Brain Research Reviews. 48(2):240-50, 2005. Progressive memory impairment, beta-amyloid (Abeta) plaques associated with local inflammation, neurofibrillary tangles, and loss of neurons in selective brain areas are hallmarks of Alzheimer's disease (AD). Although beta-amyloid precursor protein (APP) and Abeta have a central role in the etiology of AD, it is not clear which forms of APP or Abeta are responsible for the neuronal vulnerability in AD brain. Brain ischemia, another cause of dementia in the elderly, has recently been recognized to contribute to the pathogenesis of AD and individuals with severe cognitive decline and possibly underlying AD are at increased risk for ischemic events in the brain. Moreover, the epsilon4 allele of apolipoprotein E (ApoE) is a risk factor for both AD and poor outcome following brain ischemia and hemorrhage. Several factors and molecular mechanisms that lower the threshold of neuronal death in models of AD have recently been described. Among these neuroinflammation seems to play an important role. The development and maturation of both AD neuropathology and ischemic lesions in the central nervous system are characterized by activation of glial cells and upregulation of inflammatory mediators. Indeed, anti-inflammatory approaches have proven to be beneficial in the prevention and treatment of AD-like neuropathology and ischemic injuries in vivo. This review summarizes some of the findings suggesting that neuronal overexpression of human APP renders the brain more vulnerable to ischemic injury and describes the factors that are involved in increased neuronal susceptibility to ischemic stroke.