Inflammation in older subjects with early- and late-onset depression in the NESDO study: a cross-sectional and longitudinal case-only design.

OBJECTIVE: Different biological mechanisms may underlie depression beginning in early life (early-onset) and depression beginning later in life (late-onset). Although the relation between inflammation and depression has been studied extensively, the distinct role of inflammation in early and late-onset depression in older patients has not been addressed before. In the cross-sectional part of this study, we explored differences in levels of circulating inflammatory markers and cytokine levels in lipopolysaccharide (LPS) stimulated whole blood between older subjects with a late-life onset depression (≥60 years) and older subjects with an early-onset depression (<60 years). Secondly, in a 2-year follow-up study, we examined if circulating and stimulated inflammatory markers influenced the change in Inventory of Depressive Symptomatology (IDS) scores, and if this relation was different for early- and late-onset depression. METHODS: The study was part of the Netherlands Study of Depression in Older Persons (NESDO). We included 350 patients, all aged 60 and older, with a depressive episode in the previous 6 months: 119 with a late-onset depression and 231 with an early-onset depression. Blood samples were collected and CRP, IL-6, NGAL, GDF15, and, LPS plasma levels were determined and whole blood was LPS stimulated and cytokine levels IL-1ß, IL-6, TNFα, IFNγ, IL-10, and IL-1 receptor antagonist (IL-1ra) were determined. RESULTS: After adjustment for demographics, health indicators, and medication use, increased plasma CRP levels were more strongly associated with late-onset depression than early-onset depression (OR [95% CI]: 1.43 [1.05-1.94]). In the longitudinal analyses, higher circulating IL-6 levels were associated with a significantly slower decline in IDS scores in the crude and the adjusted models (p ≤ 0.027). This relation was not different between late- and early-onset depression. Other circulating and stimulated inflammatory markers were not associated with late- and/or early-onset depression. CONCLUSIONS: This study provides preliminary evidence that low-grade inflammation is more strongly associated with late-onset than early-onset depression in older adults, suggesting a distinct inflammatory etiology for late-onset depression. Cytokine production capacity did not distinguish between early- and late-onset depression.

Accumulation of BRI2-BRICHOS ectodomain correlates with a decreased clearance of Aß by insulin degrading enzyme (IDE) in Alzheimer's disease.

The precursor protein BRI2 that in its mutated form is associated with British and Danish dementia, can regulate critical processes involved in AD pathogenesis including not only the metabolism of amyloid precursor protein (APP) and formation of Aß, but also the levels of secreted insulin degrading enzyme (IDE), an enzyme involved in Aß clearance. We recently observed increased levels of a 45kDa BRI2 form as well as BRI2 ectodomain deposits in Aß plaques in human AD hippocampus, which may affect BRI2 functional activity. Since BRI2 regulated the levels of secreted IDE and subsequent degradation of Aß in human cell culture models, we explored if BRI2 changes could affect the Aß degradation capacity of IDE in human hippocampus (n=28). We observed that IDE is the main enzyme involved in Aß degradation, and both IDE levels as well as Aß degradation tend to be decreased in AD. Interestingly, the levels of the 45kDa BRI2 form and BRI2 deposits in hippocampal tissue were inversely correlated with IDE protein levels (r=-0.52, p=0.005; r=-0.4, p=0.045) and IDE activity (r=-0.5935, p=0.0004; r=-0.4, p=0.03). Taken together, the current results suggest a relationship between BRI2 protein changes, IDE activity and Aß levels in human hippocampus. Thus, the formation and accumulation high of molecular weight BRI2 forms observed in AD may impair IDE functioning and consequently lead to impaired Aß clearance and to the accumulation of Aß.

Complement activation in Glioblastoma multiforme pathophysiology: evidence from serum levels and presence of complement activation products in tumor tissue.

Inflammation plays a key role in the pathophysiology of Glioblastoma Multiforme (GBM). Here we focus on the contribution of the so far largely ignored complement system. ELISA and immunohistochemistry were combined to assess levels and localization of critical components of the initiation- and effector pathways of the complement cascade in sera and tumor tissue from GBM patients and matched controls. Serum levels of factor-B were decreased in GBM patients whereas C1q levels were increased. C1q and factor-B deposited in the tumor tissue. Deposition of C3 and C5b-9 suggests local complement activation.MBL deficiency, based on serum levels, was significantly less frequent among GBM patients compared to controls (14% vs. 33%). Therefore low levels of MBL may protect against the initiation/progression of GBM.

The early involvement of the innate immunity in the pathogenesis of late-onset Alzheimer's disease: neuropathological, epidemiological and genetic evidence.

The idea that an inflammatory process is involved in Alzheimer's disease (AD) was proposed already hundred years ago but only the past twenty years inflammation-related proteins have been identified within plaques. A number of acute-phase proteins colocalize with the extracellular amyloid fibrils, the so called Aß-associated proteins. Activated microglia and astrocytes surrounding amyloid deposits express receptors of innate immunity and secrete pro-inflammatory cytokines. In this paper we review the evidence for involvement of innate immunity in the early stages of the pathological cascade of AD. Diffuse plaques, the initial neuropathological lesion in the cerebral neocortex, contain next to Aß also apolipoprotein E, clusterin, α1-antichymotrypsin and activated complement proteins. Interestingly, genetic studies have shown gene-loci to be associated with AD for all these proteins, except α1-antichymotrpsin. Fibrillar Aß can, through stimulation of toll-like receptors and CD-14 on glial cells, activate pathways for increased production of pro-inflammatory cytokines. This pathway, inducing production of proinflammatory cytokines, is under genetic control. The finding that the responsiveness of the innate immunity is higher in offspring with a parental history of late-onset AD indicates heritable traits for AD that are related to inflammatory processes. Prospective epidemiological studies which report that higher serum levels of certain acute-phase proteins are associated with cognitive decline or dementia provide additional evidence for the early involvement of inflammation in AD pathogenesis. The reviewed neuropathological, epidemiological and genetic findings show evidence for involvement of the innate-immunity in the early stages of pathological cascade as well as for the hypothesis that the innate immunity contributes to the etiology of late-onset AD.

Soothing the inflamed brain: effect of non-steroidal anti-inflammatory drugs on Alzheimer's disease pathology.

Epidemiological studies suggest that systemic use of non-steroidal anti-inflammatory drugs (NSAIDs) can prevent or retard the development of Alzheimer's disease (AD). However, clinical trials investigating the effects of NSAIDs on AD progression have yielded mixed or inconclusive results. The aim of this review is to distinguish the role of inflammation and the molecular targets of NSAIDs in the different stages of AD pathology. AD brains are characterized by extracellular deposits of ß-amyloid protein and intraneuronal accumulation of hyperphosphorylated tau protein. Already in the early stages of AD pathology ß-amyloid protein deposits are associated with inflammatory proteins and microglia, the brain resident macrophages. Recently, two genome-wide association studies identified new genes that are associated with an increased risk of developing AD. These genes include CLU and CR1 which encode for clusterin and complement receptor 1 respectively. Both genes are involved in the regulation of inflammation. This strongly indicates that inflammation plays a central role in the aetiology of AD. In this review we will show that the primary targets of NSAIDs are involved in a pathological stage that precedes the clinical appearance of AD. The early, preclinical involvement of inflammation in AD explains why patients with clinical signs of AD do not benefit from anti-inflammatory treatment and suggests that NSAIDs, rather than having a direct therapeutic effect, may have preventive effects.

Brain-specific fatty acid-binding protein is elevated in serum of patients with dementia-related diseases.

BACKGROUND: There is a need for biomarkers in accessible matrices, such as blood, for the diagnosis of neurodegenerative diseases. The aim of this study was to measure the serum levels of brain-type fatty acid-binding protein (FABP) and heart-type FABP in patients with dementia-involving diseases. METHODS: Brain- and heart-type FABP were measured in serum samples from patients with either Alzheimer's disease (AD) (n = 31), Parkinson's disease (PD, n = 43), or other cognitive disorders (OCD, n = 42) and in 52 healthy controls. The localization of brain- and heart-type FABP was determined in brain sections by immunohistochemistry. RESULTS: Brain-type FABP levels were elevated in serum of 29%, 35%, and 24% of the patients with AD, PD, and OCD, respectively, and in 2% of the healthy donors. Heart-type FABP serum levels were not different amongst the patient groups. Brain-type and heart-type FABP expression was observed in reactive astrocytes in brain sections of patients with AD. CONCLUSIONS: In contrast to heart-type FABP, serum levels of brain-type FABP are elevated in a significant proportion of patients with various neurodegenerative diseases and can therefore have importance for defining subgroups of these patients.

Increased Abeta1-42 production sensitizes neuroblastoma cells for ER stress toxicity.

Alzheimer's disease (AD) is characterized by the aggregation and subsequent deposition of misfolded beta-amyloid (Abeta) peptide. The unfolded protein response (UPR) is activated by misfolded protein stress in the endoplasmic reticulum (ER). In previous studies we demonstrated mild activation of the UPR by extracellularly applied oligomeric but not fibrillar Abeta1-42. In addition, we showed that oligomeric Abeta1-42 is internalized by cells, whereas fibrillar Abeta1-42 remains on the outside of the cell. Inhibition of Abeta uptake specifically inhibits toxicity of Abeta1-42 oligomers, underscoring the toxic potential of intracellular Abeta. Therefore, in the present study, we investigated the connection between intracellularly produced Abeta and the ER stress response, using human neuroblastoma cells overexpressing either wild type APP695 (APPwt) or APP695V717F (APPmut). Both cell lines secrete higher levels of Abeta1-40 and Abeta1-42 compared to the parental line. In addition, APPmut produces more Abeta1-42 than APPwt. Whereas the basal levels of UPR markers are not different, we find augmented UPR induction in response to ER stress in both APP overproducing cell lines compared to the parental cell line, with the strongest UPR activation in APPmut cells. In addition, ER stress toxicity was highest in APPmut cells, strongly suggesting a connection with the production of Abeta1-42. The difference in ER stress mediated toxicity between the APPwt and APPmut cell lines is alleviated by pretreatment with gamma-secretase inhibitor, indicating that it is dependent on Abeta production and in particular on Abeta1-42. Our data indicate that increased Abeta1-42 production sensitizes neuroblastoma cells for ER stress toxicity.

Cyclooxygenase-1 and -2 in the different stages of Alzheimer's disease pathology.

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.

Decreased cerebrospinal fluid amyloid beta (1-40) levels in frontotemporal lobar degeneration.

The role of amyloid metabolism in the pathophysiology of frontotemporal lobar degeneration (FTLD) has yet to be elucidated. We compared CSF levels of amyloid beta 1-40 (Abeta40) and amyloid beta 1-42 (Abeta42) in patients with FTLD (n = 21) versus patients with Alzheimer's disease (AD, n = 39) and in control subjects (n = 30). While in AD cases Abeta42 levels were lower and CSF Abeta40 levels equal to those in controls, a significant decrease in Abeta40 and increase in the CSF Abeta42/Abeta40 ratio was observed in FTLD compared with AD and control subjects. These findings favour a differential involvement of amyloid beta peptides in FTLD compared with AD.

The significance of neuroinflammation in understanding Alzheimer's disease.

The interest of scientists in the involvement of inflammation-related mechanisms in the pathogenesis of Alzheimer's disease (AD) goes back to the work of one of the pioneers of the study of this disease. About hundred years ago Oskar Fischer stated that the crucial step in the plaque formation is the extracellular deposition of a foreign substance that provokes an inflammatory reaction followed by a regenerative response of the surrounding nerve fibers. Eighty years later immunohistochemical studies revealed that amyloid plaques are indeed co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. These findings have led to the view that the amyloid plaque is the nidus of a non-immune mediated chronic inflammatory response locally induced by fibrillar A beta deposits. Recent neuropathological studies show a close relationship between fibrillar A beta deposits, inflammation and neuroregeneration in relatively early stages of AD pathology preceding late AD stages characterized by extensive tau-related neurofibrillary changes. In the present work we will review the role of inflammation in the early stage of AD pathology and particularly the role of inflammation in A beta metabolism and deposition. We also discuss the possibilities of inflammation-based therapeutic strategies in AD.

Neuroinflammation and regeneration in the early stages of Alzheimer's disease pathology.

The initial stages of Alzheimer's disease pathology in the neocortex show upregulation of cell cycle proteins, adhesion and inflammation related factors, indicating the early involvement of inflammatory and regenerating pathways in Alzheimer's disease pathogenesis. These brain changes precede the neurofibrillary pathology and the extensive process of neurodestruction and (astro)gliosis. Amyloid beta deposition, inflammation and regenerative mechanisms are also early pathogenic events in transgenic mouse models harbouring the pathological Alzheimer's disease mutations, while neurodegenerative characteristics are not seen in these models. This review will discuss the relationship between neuroinflammation and neuroregeneration in the early stages of Alzheimer's disease pathogenesis.

Amyloid associated proteins in Alzheimer's and prion disease.

Clustering of activated microglia in Abeta deposits is related to accumulation of amyloid associated factors and precedes the neurodegenerative changes in AD. Microglia-derived pro-inflammatory cytokines are suggested to be the driving force in AD pathology. Inflammation-related proteins, including complement factors, acute-phase proteins, pro-inflammatory cytokines, that normally are locally produced at low levels, are increasingly synthesized in Alzheimer's disease (AD) brain. Similar to AD, in prion diseases (Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease and experimentally scrapie infected mouse brain) amyloid associated factors and activated glial cells accumulate in amyloid deposits of conformational changed prion protein (PrPres). Biological properties of Abeta and prion (PrP) peptides, including their potential to activate microglia, relate to Abeta and PrP peptide fibrillogenic abilities that are influenced by certain amyloid associated factors. However, since small oligomers of amyloid forming peptides are more toxic to neurons than large fibrils, certain amyloid associated factors that enhance fibril formation, may sequester the potentially harmful Abeta and PrP peptides from the neuronal microenvironment. In this review the positive and negative actions of amyloid associated factors on amyloid peptide fibril formation and on the fibrillation state related activation of microglia will be discussed. Insight in these mechanisms will enable the design of specific therapies to prevent neurodegenerative diseases in which amyloid accumulation and glial activation are prominent early features.

The unfolded protein response is activated in Alzheimer's disease.

Alzheimer's disease (AD) is, at the neuropathological level, characterized by the accumulation and aggregation of misfolded proteins. The presence of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the unfolded protein response (UPR) that may protect the cell against the toxic buildup of misfolded proteins. In this study we investigated the activation of the UPR in AD. Protein levels of BiP/GRP78, a molecular chaperone which is up-regulated during the UPR, was found to be increased in AD temporal cortex and hippocampus as determined by Western blot analysis. At the immunohistochemical level intensified staining of BiP/GRP78 was observed in AD, which did not co-localize with AT8-positive neurofibrillary tangles. In addition, we performed immunohistochemistry for phosphorylated (activated) pancreatic ER kinase (p-PERK), an ER kinase which is activated during the UPR. p-PERK was observed in neurons in AD patients, but not in non-demented control cases and did not co-localize with AT8-positive tangles. Overall, these data show that the UPR is activated in AD, and the increased occurrence of BiP/GRP78 and p-PERK in cytologically normal-appearing neurons suggest a role for the UPR early in AD neurodegeneration. Although the initial participation of the UPR in AD pathogenesis might be neuroprotective, sustained activation of the UPR in AD might initiate or mediate neurodegeneration.

C-reactive protein and complement depositions in human infarcted myocardium are more extensive in patients with reinfarction or upon treatment with reperfusion.

BACKGROUND: Impaired perfusion of the heart induces a local inflammatory response, which involves deposition of C-reactive protein and complement activation products C3d and C5b-9. We investigated whether reperfusion or reinfarction enhances these phenomena in humans. MATERIALS AND METHODS: Depositions of C-reactive protein and complement were quantified in tissue samples of infarcted myocardium from 76 patients who had died after acute myocardial infarction. The extent of depositions in patients treated with reperfusion or suffering from reinfarction was compared with that in patients who had no reperfusion or reinfarction. RESULTS: Patients with reinfarction had significantly more extensive depositions of C-reactive protein and complement (C3d and C5b-9) in the infarcted myocardium than patients without reinfarction. Similarly, patients who received reperfusion therapy had more extensive depositions also than those who had not received this therapy. CONCLUSIONS: Both reinfarction and reperfusion therapy significantly increase the extent of C-reactive protein and complement depositions in human myocardial infarcts.

Decreased lysophosphatidylcholine/phosphatidylcholine ratio in cerebrospinal fluid in Alzheimer's disease.

Choline containing phospholipids are essential for the integrity of the'cell'membrane. Minor changes in the lysophosphatidylcholine (lyso-PC)/phosphatidylcholine (PC) ratio may lead to neuronal damage and cell loss. Several studies have shown protein and lipid oxidation in Alzheimer's disease (AD) affected brain regions. Amyloid-beta peptides may induce free-radical oxidative stress which normally is counteracted by anti-oxidant defense mechanisms. We hypothesize that oxidation may lead to changed concentrations of choline containing phospholipids in cerebrospinal fluid (CSF) of AD patients, because of the susceptibility of the unsaturated acyl-chains of PC for oxidation. PC and lyso-PC were determined in CSF of AD patients (n=19) and subjects with subjective memory complaints without dementia (n=19) by tandem mass spectrometry. No differences in total PC concentrations were observed between both study groups. Furthermore, we could not demonstrate different concentrations of PC species containing linoleic acid and PC species containing arachidonic acid. Interestingly, lyso-PC concentrations tended to be lower while the lyso-PC/PC ratio was significantly decreased in CSF of AD patients compared to controls (0.36% versus 0.54%; P=0.017). A comparable decrease was found for the lyso-PC/PC ratio for PC containing linoleic acid (P=0.022) or arachidonic acid (P=0.010), respectively. The lower lyso-PC/PC ratio in CSF of patients with AD may reflect alterations in the metabolism of choline-containing phospholipids in the brain in AD, and suggests that PC species containing linoleic acid or arachidonic acid are equally involved.

CSF markers related to pathogenetic mechanisms in Alzheimer's disease.

Serum amyloid P component (SAP) and complement C1q are found highly co-localized with extracellular fibrillar amyloidbeta (Abeta) deposits in Alzheimer's disease (AD) brain. Conflicting data were reported earlier about the cerebrospinal fluid (CSF) levels of SAP and C1q in AD compared to controls. The objective of the present study was to compare the levels of Abeta(1-42), tau, C1q and SAP in CSF of a well characterized group of AD patients and controls, and to assess the association with dementia severity. Significantly decreased CSF levels of Abeta(1-42) were observed in the AD group (480 +/- 104 ng/L) as compared to controls (1,040 +/- 213 ng/L), whereas tau levels were significantly higher in patients with AD (618 +/- 292 ng/L) than in controls (277 +/- 136 ng/L). Combining the results of Abeta(1-42) and tau measurements resulted in a clear separation between the AD group and the controls. No significant differences in CSF levels of SAP and C1q were observed between the well characterized AD patients and non demented control group. Furthermore, we could not demonstrate a correlation between SAP and C1q CSF levels and the severity of the disease, expressed in Mini-Mental State Examination (MMSE) scores. Therefore, in our opinion these factors can be excluded from the list of potentially interesting biomarkers for AD diagnosis and progression.

Neuroinflammation in Alzheimer's disease and prion disease.

Alzheimer's disease (AD) and prion disease are characterized neuropathologically by extracellular deposits of Abeta and PrP amyloid fibrils, respectively. In both disorders, these cerebral amyloid deposits are co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase protein, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that the cerebral Abeta and PrP deposits are closely associated with a locally induced, non-immune-mediated chronic inflammatory response. Epidemiological studies indicate that polymorphisms of certain cytokines and acute-phase proteins, which are associated with Abeta plaques, are genetic risk factors for AD. Transgenic mice studies have established the role of amyloid associated acute-phase proteins in Alzheimer amyloid formation. In contrast to AD, there is a lack of evidence that cytokines and acute-phase proteins can influence disease progression in prion disease. Clinicopathological and neuroradiological studies have shown that activation of microglia is a relatively early pathogenetic event that precedes the process of neuropil destruction in AD patients. It has also been found that the onset of microglial activation coincided in mouse models of prion disease with the earliest changes in neuronal morphology, many weeks before neuronal loss and subsequent clinical signs of disease. In the present work, we review the similarities and differences between the involvement of inflammatory mechanisms in AD and prion disease. We also discuss the concept that the demonstration of a chronic inflammatory-like process relatively early in the pathological cascade of both diseases suggests potential therapeutic strategies to prevent or to retard these chronic neurodegenerative disorders.

Establishment of microglial cell cultures derived from postmortem human adult brain tissue: immunophenotypical and functional characterization.

Cell cultures have become an integral part of the daily routine in most biological research laboratories. Because they are very dynamic and highly accessible, cell cultures permit direct experimental manipulations where cause-effect relations can be more definitely assayed. We have developed cultures of microglial cells from rapid autopsies (range 3-10 hours) of nondemented elderly patients and Alzheimer's disease patients. Cultures were derived from the subcortical white matter, corpus callosum, and frontal, temporal, and occipital cortex. The adherent microglial cells were immunoreactive for CD68, CD45, CD11c, and major histocompatibility complex (MHC) class II markers, and were not immunoreactive for astrocyte or oligodendrocyte markers. In addition, some functional characteristics of the isolated microglial cells were also studied. Upon stimulation with lipopolysaccharide (LPS), microglial cells secreted pro- and antiinflammatory mediators, i.e., interleukin- (IL)-6, prostaglandin E2 (PGE2), and IL-10, indicating the functional capacity of cultured microglia.

Immunological aspects of alzheimer's disease: therapeutic implications.

Alzheimer's disease (AD) is a chronic neurodegenerative disease causing progressive impairment of memory and cognitive function. The amyloid cascade hypothesis suggests that mismetabolism of the beta-amyloid (A beta) precursor protein (APP) followed by subsequent formation of non-fibrillar and fibrillar A beta deposits leads to glial activation and eventually to neurotoxicity, causing cognitive impairment. Several lines of evidence indicate that an inflammatory process contributes to the pathology of AD. First, inflammatory proteins have been identified as being associated with neuritic plaques and in glial cells surrounding these plaques. Second, certain polymorphisms of acute-phase proteins and cytokines associated with AD plaques increase the risk or predispose for earlier onset of developing AD. Third, epidemiological studies indicate that anti-inflammatory drugs can retard the development of AD. Several steps in the pathological cascade of AD have been identified as possible targets for actions of nonsteroidal anti-inflammatory drugs. For instance, microglia are considered a target because this cell type is closely involved in AD pathology through secretion of neurotoxic substances and by modulating a positive feedback loop of the inflammatory mechanism that may be involved in the pathological cascade in AD. On the basis of studies in APP transgenic mice, immunisation with A beta was recently suggested as a novel immunological approach for the treatment of AD. Immunisation elicits A beta-specific antibodies that could affect several early steps of the amyloid-driven cascade. Antibodies could prevent A beta from aggregating into fibrils and accelerate clearance of A beta by stimulating its removal by microglial cells. This review outlines the pathological and genetic evidence that an inflammatory mechanism is involved in AD and the therapeutic approaches based on inhibition or mediation of inflammation.