amyloid-beta-peptides and Inflammation

Extensive data point to the immune system as an important factor underlying the pathogenesis of brain diseases. Epidemiological studies have shown that long-term treatment with non-steroidal anti-inflammatory drugs (NSAIDs) significantly reduces the onset and progression of Alzheimer's disease. The present study aimed to investigate whether ibuprofen (IBU) is able to prevent the long-lasting alterations of brain function induced by systemic inflammation.. Mice received intraperitoneal injections of lipopolysaccharide (LPS; 250 µg/kg/day) for seven consecutive days. Ibuprofen administration (40 mg/kg/day) was started three days before the LPS injections and continued until the last day of LPS injection. Within the next 2 weeks, mice performances on the behavioral tests were evaluated, and then brain tissue samples for biochemical analyses were collected.. The findings showed that ibuprofen significantly improved mice's performance in the passive avoidance test and reduced anxiety- and depressive-like behaviors. However, ibuprofen could not significantly improve spatial memory in the Morris water maze test and recognition ability in the novel object recognition test. TNF-α and IL-1β cytokines levels and malondialdehyde (MDA) concentration in the hippocampal tissues of LPS-treated mice were significantly lowered by ibuprofen treatment, whereas no significant effects on IL-10 production and hippocampal BDNF levels were observed. In addition, ibuprofen did not significantly reduce amyloid-β. Overall, the findings of the present study suggest that some, but not all, of the adverse effects of systemic inflammation are alleviated by ibuprofen treatment.

Topics: Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anxiety; Behavior, Animal; Brain; Cytokines; Depression; Encephalitis; Ibuprofen; Inflammation; Lipopolysaccharides; Male; Malondialdehyde; Memory Disorders; Mice; Mice, Inbred BALB C; Morris Water Maze Test; Peptide Fragments; Psychomotor Performance; Recognition, Psychology; Swimming

Since westernized diet-induced insulin resistance is a risk factor in Alzheimer's disease (AD) development, and lipopolysaccharide (LPS) coexists with amyloid β (Aβ)1-42 in these patients, our AD novel model was developed to resemble sporadic AD by injecting LPS into high fat/fructose diet (HFFD)-fed rats. The neuroprotective potential of palonosetron and/or methyllycaconitine, 5-HT3 receptor and α7 nAChR blockers, respectively, was evaluated after 8 days of daily administration in HFFD/LPS rats. All regimens improved histopathological findings and enhanced spatial memory (Morris Water Maze); however, palonosetron alone or with methyllycaconitine promoted animal performance during novel object recognition tests. In the hippocampus, all regimens reduced the expression of glial fibrillary acidic protein and skewed microglia M1 to M2 phenotype, indicated by the decreased M1 markers and the enhanced M2 related parameters. Additionally, palonosetron and its combination regimen downregulated the expression of ASC/TMS1, as well as levels of inflammasome downstream molecules and abated cleaved caspase-1, interleukin (IL)-1β, IL-18 and caspase-11. Furthermore, ACh and 5-HT were augmented after being hampered by the insult. Our study speculates that blocking 5-HT3 receptor using palonosetron overrides methyllycaconitine to combat AD-induced neuroinflammation and inflammasome cascade, as well as to restore microglial function in a HFFD/LPS novel model for sporadic AD.

Topics: Aconitine; Alzheimer Disease; Amyloid beta-Peptides; Animals; CARD Signaling Adaptor Proteins; Cognition; Diet, Western; Disease Models, Animal; Hippocampus; Humans; Inflammasomes; Inflammation; Insulin Resistance; Interleukin-18; Lipopolysaccharides; Microglia; Palonosetron; Peptide Fragments; Pyroptosis; Rats; Receptors, Serotonin, 5-HT3; Risk Factors; Spatial Memory

Microglia have a pivotal role to initiate immune responses in AD brains through toll-like receptors and induce neuroinflammation. Adipose tissue mesenchymal stem cells (ATSCs) secret many neurotrophic and anti-inflammatory factors called conditioned medium (CM). Many studies have demonstrated that CM of mesenchymal stem cells facilitate regeneration and attenuates inflammation in many disorders. To this purpose, the effect of ATSCs-conditioned medium (ATSC-CM) on brain inflammation and the role of toll-like receptors were investigated in this study. Seventy-two rats were randomly divided into 6 groups: control, sham, sham+ATSC-CM: 200μl ATSC-CM once a day intraperitoneally for 8 days, AD group injected the Aβ1-40 intra-hippocampal, AD+ASC-CM, which was injected Aβ1-40 intra-hippocampal and 200μl ATSC-CM once a day intraperitoneally for 8 days and AD+ rivastigmine: was injected Aβ1-40 intra-hippocampal and received rivastigmine (0.6 mg/kg) orally once a day for 2 weeks. Memory and learning were measured by Morris water maze and novel object recognition tests. For detection of beta-amyloid plaque, Congo red staining was used, and neuronal survival was assessed by Nissl staining. Expression of TLR2 and TLR4 was measured by real-time PCR, and finally, to assess inflammation markers (IL-1β and TNF-α) in the hippocampus, ELISA kits were used. In treatment group spatial and recognition memory significantly was improved. ATSC-CM administration decreased beta amyloid plaques and enhanced neuronal survival in AD brain rats. In addition, TLR2 and TLR4 expression decreased in treatment group. Results also showed that ATSC-CM reduced IL-1β and TNF-α as inflammation markers. ATSC-CM improved memory deficit, decreased beta amyloids formation, increased neuron survival, and attenuated inflammation by reducing the expression of TLRs.

Topics: Adipose Tissue; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cholinesterase Inhibitors; Culture Media, Conditioned; Disease Models, Animal; Hippocampus; Hypoxia; Inflammation; Interleukin-1beta; Learning; Male; Maze Learning; Mesenchymal Stem Cells; Peptide Fragments; Rats; Rats, Wistar; Recognition, Psychology; Rivastigmine; Spatial Memory; Toll-Like Receptor 2; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive impairments. Vitegnoside is a flavonoid present in the medicinal plant Vitex negundo, widely used as a folk medicine in several Asian countries including China. It possesses several biological activities, including axon outgrowth, but no evidence is available on its effect on AD. Since no effective treatment is available to cure AD, the effect of vitegnoside on this disease was investigated. The human neuroblastoma SH-SY5Y cell line carrying the Swedish mutation that induces AβPP overexpression was used as an in vitro AD cell model. AβPP overexpression does not induce toxicity per se unless triggered by copper. Vitegnoside promoted neuroprotection through the improvement of cell viability, maintenance of cytomembrane integrity and nuclear homogeneity in these cells, but these effects were not observed in the copper-treated SH-SY5Y cells without AβPP overexpression used as the wild-type control, indicating that vitegnoside exerted neuroprotection under copper-triggered Aβ toxic conditions. Vitegnoside failed to decrease AβPP expression, Aβ40/42 levels, and oxidative stress due to copper-induced Aβ toxicity. However, its administration protected the mitochondrial function and restored the imbalance between pro-apoptotic and anti-apoptotic proteins. Additionally, vitegnoside inactivated p38 MAPK/MK2, JNK/c-Jun, and downstream NF-κB inflammatory transductions. Furthermore, the inactivation of p38 MAPK/JNK signaling contributed to vitegnoside-mediated neuroprotection resulting from pharmacological inhibition of p38 MAPK/JNK and in silico interaction prediction. Our study revealed the neuroprotective effect of vitegnoside and its potential mechanisms against copper-induced Aβ neurotoxicity. These findings highlighted the potential therapeutic effect of vitegnoside against AD progression.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Apoptosis; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Flavonoids; Humans; Inflammation; Inflammation Mediators; MAP Kinase Signaling System; Mitochondria; Neurons; Neuroprotective Agents; p38 Mitogen-Activated Protein Kinases; Peptide Fragments; Vitex

The roots of Achyranthes bidentata Blume (AB) is commonly used in the treatment of osteoporosis and dementia in traditional Chinese medicine. Pharmacological reports evidenced that AB possessed anti-osteoarthritis effects. However, there is little literature about the anti-dementia activities of AB. The present study was designed to prepare steroid-enriched fraction of AB (ABS) and investigate whether ABS can protect from cognitive dysfunction and neuroinflammation against Aβ 1-40-induced Alzheimer's disease (AD) model in rats. ABS only contained 135.11 ± 4.28 mg of ecdysterone per gram. ABS (50 mg/kg) reversed the dysfunction of exploratory activity and memory function on plus-maze and Morris water maze caused by Aβ 1-40 in rats. ABS (50 mg/kg) also decreased amyloid deposition, neurofibrillary tangle, neural damage, activated astrocyte, and microglial caused by Aβ 1-40. Furthermore, ABS reversed the phenomenon of neural oxidative damage and neuroinflammation, including the higher levels of MDA and cytokines, and the lower activities of antioxidant enzymes and GSH levels caused by Aβ 1-40 in rat cortex and hippocampus. Finally, ABS restored the activation of ERK pathway and decreased NF-κB phosphorylation and translocation altered by Aβ 1-40. ABS alone (50 mg/kg) promoted cognitive function, activated brain antioxidant defense system, and decreased brain TNF-α levels in sham group. Therefore, ABS has the cognition-promoting and antidementia potential. Steroids especial ecdysterone are major active components of AB. The action mechanism is due to decreasing oxidative stress and neuroinflammation through modulating ERK pathway, NF-κB phosphorylation, and translocation in Aβ 1-40-induced AD rat model.

Topics: Acetylcholinesterase; Achyranthes; Amyloid beta-Peptides; Animals; Antioxidants; Astrocytes; Behavior, Animal; Brain; Cognitive Dysfunction; Cytokines; Ecdysterone; Glutathione; Hippocampus; Inflammation; Male; Malondialdehyde; MAP Kinase Signaling System; Maze Learning; Memory; Microglia; Neuroprotective Agents; NF-kappa B; Oleanolic Acid; Peptide Fragments; Rats, Sprague-Dawley; Steroids; Triterpenes; Ursolic Acid

Immunotherapies are a promising strategy for the treatment of neurological diseases such as Alzheimer's disease (AD), however, transport of antibodies to the brain is severely restricted by the blood-brain barrier (BBB). Furthermore, molecular transport at the BBB is altered in disease, which may affect the mechanism and quantity of therapeutic antibody transport. To better understand the transport of immunotherapies at the BBB in disease, an in vitro BBB model derived from human induced pluripotent stem cells (iPSCs) was used to investigate the endocytic uptake route of immunoglobulin G (IgG). In this model, uptake of fluorescently labeled IgGs is a saturable process. Inhibition of clathrin-mediated endocytosis, caveolar endocytosis, and macropinocytosis demonstrated that macropinocytosis is a major transport route for IgGs at the BBB. IgG uptake and transport were increased after the addition of stimuli to mimic AD (Aβ

Topics: Amyloid beta-Peptides; Blood-Brain Barrier; Cell Line; Cytokines; Humans; Immunoglobulin G; Inflammation; Models, Biological; Peptide Fragments; Protein Transport

Amyloid-β (Aβ) plays a critical role in the pathogenesis of Alzheimer's disease (AD), an age-related neurodegenerative ailment. Emerging evidence suggests that Tenuifolin (TEN) significantly decreases Aβ secretion and relieves cellular inflammatory responses. However, the mechanism of this activity has not been fully elucidated. In the present study, we investigate the effect of TEN on autophagy, a process that plays an important role in the generation and metabolism of Aβ, in the presence or absence of the autophagy inhibitor 3-MA. The obtained results show that TEN prevents Aβ25-35-induced inflammation and decreases Aβ1-40 and Aβ1-42 levels by decreasing BACE1 in SH-SY5Y cells. Moreover, TEN decreases the mRNA levels of BACE1 but has no impact on the gene expressions of amyloid precursor proteins (APP). 3-MA, the most widely used autophagy inhibitor, reverses the effects of TEN in Aβ25-35-induced SH-SY5Y cells. The association between TEN and autophagy was further investigated by examining the levels of autophagy markers LC3 II and Beclin 1, as well as the protein levels of mTOR, AMPK, and ULK1. The results showed that TEN increases LC3 II, Beclin 1, and mTOR, inhibits the degradation of AMPK, and increases the expression of ULK1. This suggests that TEN protects against Aβ25-35-induced cellular inflammation in an AD cell model through the regulation of autophagy, which, in part, is mediated by the activation of the AMPK/mTOR/ULK1 pathway.

Topics: Adenine; Alzheimer Disease; AMP-Activated Protein Kinases; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Apoptosis; Aspartic Acid Endopeptidases; Autophagy; Autophagy-Related Protein-1 Homolog; Beclin-1; Cell Line, Tumor; Cell Survival; Diterpenes, Kaurane; Humans; Inflammation; Intracellular Signaling Peptides and Proteins; Microtubule-Associated Proteins; Neuroprotective Agents; Peptide Fragments; TOR Serine-Threonine Kinases

A catecholamine neurotransmitter, dopamine (DA), is suggested to be linked to the pathology of dementia; however, the involvement of DA and its structural analogues in the pathogenesis of Alzheimer's disease (AD), the most common form of dementia, composed of multiple pathogenic factors has not been clear. Herein, we report that DA and its rationally designed structural derivatives (1-6) based on DA's oxidative transformation are able to modulate multiple pathological elements found in AD [i.e., metal ions, metal-free amyloid-β (Aβ), metal-bound Aβ (metal-Aβ), and reactive oxygen species (ROS)], with demonstration of detailed molecular-level mechanisms. Our multidisciplinary studies validate that the protective effects of DA and its derivatives on Aβ aggregation and Aβ-mediated toxicity are induced by their oxidative transformation with concomitant ROS generation under aerobic conditions. In particular, DA and the derivatives (i.e., 3 and 4) show their noticeable anti-amyloidogenic ability toward metal-free Aβ and/or metal-Aβ, verified to occur via their oxidative transformation that facilitates Aβ oxidation. Moreover, in primary pan-microglial marker (CD11b)-positive cells, the major producers of inflammatory mediators in the brain, DA and its derivatives significantly diminish inflammation and oxidative stress triggered by lipopolysaccharides and Aβ through the reduced induction of inflammatory mediators as well as upregulated expression of heme oxygenase-1, the enzyme responsible for production of antioxidants. Collectively, we illuminate how DA and its derivatives could prevent multiple pathological features found in AD. The overall studies could advance our understanding regarding distinct roles of neurotransmitters in AD and identify key interactions for alleviation of AD pathology.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Copper; Dopamine; Humans; Inflammation; Metals; Microglia; Oxidative Stress; Peptide Fragments; Protein Aggregation, Pathological; Reactive Oxygen Species; Zinc

To investigate whether activation of the liver X receptors (LXRs) inhibits amyloid β. Confluent cultures of human primary RPE and ARPE-19 cells pretreated with 5 μΜ of TO901317 (TO90), a synthetic agonist of LXR, or vehicle were incubated with 1 μΜ of Aβ. A negative linear relationship between the Aβ. Activation of the LXRα-ABCA1 axis may alleviate Aβ

Topics: Amyloid beta-Peptides; Cell Line; Cell Survival; Cells, Cultured; Cellular Senescence; Cytokines; Epithelial Cells; Humans; Hydrocarbons, Fluorinated; Inflammation; Liver X Receptors; Macular Degeneration; NF-kappa B; Peptide Fragments; Retinal Pigment Epithelium; Sulfonamides

Ghrelin is a metabolic hormone that has neuroprotective actions in a number of neurological conditions, including Parkinson's disease (PD), stroke and traumatic brain injury. Acyl ghrelin treatment in vivo and in vitro also shows protective capacity in Alzheimer's disease (AD). In the present study, we used ghrelin knockout (KO) and their wild-type littermates to test whether or not endogenous ghrelin is protective in a mouse model of AD, in which human amyloid β peptide 1-40 (Aβ

Topics: Amyloid beta-Peptides; Animals; Cognition; Disease Models, Animal; Ghrelin; Inflammation; Maze Learning; Mice; Mice, Knockout; Neuronal Plasticity; Orientation, Spatial; Peptide Fragments

Amyloid-beta (Aβ) is a hallmark component of age-related macular degeneration (AMD), which induces secretion of pro-inflammatory cytokines from retinal pigment epithelium (RPE). Previous studies have shown that p50/RelA (p65), a member of NF-κB family, is an essential pro-inflammatory transcription factor responding to Aβ

Topics: Amyloid beta-Peptides; Animals; Cells, Cultured; Electroretinography; Gene Expression Regulation; Inflammation; Macular Degeneration; Male; Mice; Mice, Inbred C57BL; NF-kappa B p50 Subunit; Peptide Fragments; Proto-Oncogene Proteins c-rel; Retinal Pigment Epithelium; RNA Interference; RNA, Small Interfering; Transcription Factor RelA; Transcription Factor RelB

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by welldefined neuropathological brain changes including amyloid plaques, neurofibrillary tangles and the presence of chronic neuroinflammation.. The brain penetrant BET bromodomain inhibitor JQ1 has been shown to regulate inflammation responses in vitro and in vivo, but its therapeutic potential in AD is currently unknown.. Three-month-old 3xTg mice were injected once a day with JQ1 (50 mg/kg) or vehicle for 15 weeks. At the end of the treatment learning and memory was assessed using the modified Barnes maze and the Y maze behavioral tests. Tissue from the brain and other organs was collected for molecular evaluation of neuroinflammation tau pathology and amyloid β.. JQ1 treatment reduced splenomegaly and neuroinflammation in the brain of treated mice where we observed a reduction in the expression of the pro-inflammatory modulators Il-1b, Il-6, Tnfa, Ccl2, Nos2 and Ptgs2. Additionally, JQ1-treated mice showed a reduction of tau phosphorylation at Ser396 in the hippocampus and frontal cortex while total levels of tau remained unaffected. On the other hand, JQ1 did not ameliorate learning and memory deficits in 7-month-old 3xTg mice.. Taken together, our data suggest that BET bromodomain inhibitors hold the promise to be used for the treatment of neurological disorders characterized by neuroinflammation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Azepines; Brain; Disease Models, Animal; Drug Evaluation, Preclinical; Inflammation; Learning; Male; Memory; Mice, Transgenic; Neuroprotective Agents; Organ Size; Peptide Fragments; Phosphorylation; Spleen; tau Proteins; Triazoles

Electroconvulsive therapy (ECT) is an effective treatment for depression, but can result in memory deficits. This study aimed to determine whether ketamine could alleviate electroconvulsive shock (ECS, an analog of ECT in animals)-induced memory impairment and the potential molecular mechanism. Chronic unpredictable mild stress was used to generate animal models of depressive-like symptoms. Sixty adult male Sprague-Dawley rats were randomly divided into the following five groups: control group (group C); depressive-like model group (group D); ECS group (group DE); ketamine+ECS group (group DKE); and ketamine group (group DK). The sucrose preference test and Morris water maze were used to assess behavioral changes. The expression levels of Iba-1, IL-1β and TNF-α were measured by immunohistochemistry and real-time PCR. Enzyme-linked immunosorbent assays were used to detect the levels of soluble Aβ. We found that ECS up-regulated the expression of Iba-1, promoted the release of IL-1β and TNF-α, increased the levels of Aβ1-40 and Aβ1-42 in the hippocampus, and aggravated memory impairment of the depressive-like rats. However, ketamine reversed these ECS-induced molecular changes and effectively attenuated ECS-induced memory impairment. This cognitive protective effect of ketamine may be attributed to its suppression of ECS-induced neuroinflammation and reduction of the levels of soluble Aβ.

Topics: Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Calcium-Binding Proteins; Depression; Electroshock; Hippocampus; Inflammation; Interleukin-1beta; Ketamine; Male; Maze Learning; Memory Disorders; Microfilament Proteins; Peptide Fragments; Rats, Sprague-Dawley; RNA, Messenger; Solubility; Tumor Necrosis Factor-alpha

Several studies have shown that the accumulation of β-amyloid peptides in the brain parenchyma or vessel wall generates an inflammatory environment. Some even suggest that there is a cause-and-effect relationship between inflammation and the development of Alzheimer's disease and/or cerebral amyloid angiopathy (CAA). Here, we studied the ability of wild-type Aβ1-40 -peptide (the main amyloid peptide that accumulates in the vessel wall in sporadic forms of CAA) to modulate the phenotypic transition of vascular smooth muscle cells (VSMCs) toward an inflammatory/de-differentiated state. We found that Aβ1-40 -peptide alone neither induces an inflammatory response, nor decreases the expression of contractile markers; however, the inflammatory response of VSMCs exposed to Aβ1-40 -peptide prior to the addition of the pro-inflammatory cytokine IL-1β is greatly intensified compared with IL-1β-treated VSMCs previously un-exposed to Aβ1-40 -peptide. Similar conclusions could be drawn when tracking the decline of contractile markers. Furthermore, we found that the mechanism of this potentiation highly depends on an Aβ1-40 preactivation of the PI3 Kinase and possibly NFκB pathway; indeed, blocking the activation of these pathways during Aβ1-40 -peptide treatment completely suppressed the observed potentiation. Finally, strengthening the possible in vivo relevance of our findings, we evidenced that endothelial cells exposed to Aβ1-40 -peptide generate an inflammatory context and have similar effects than the ones described with IL-1β. These results reinforce the idea that intraparietal amyloid deposits triggering adhesion molecules in endothelial cells, contribute to the transition of VSMCs to an inflammatory/de-differentiated phenotype. Therefore, we suggest that acute inflammatory episodes may increase vascular alterations and contribute to the ontogenesis of CAA.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cell Dedifferentiation; Cells, Cultured; Cerebral Amyloid Angiopathy; Culture Media, Conditioned; Enzyme Activation; Inflammation; Interleukin-1beta; Mice; Muscle, Smooth, Vascular; NF-kappa B; Peptide Fragments; Phosphatidylinositol 3-Kinases

We studied longitudinal changes of the levels of anti-amyloid β (anti-Aβ) antibody, amyloid β (Aβ) protein, and interleukin 8 (IL-8) in cerebrospinal fluid (CSF) of a patient with cerebral amyloid angiopathy-related inflammation (CAA-ri) in whom steroid treatment resulted in clinical improvement. The diagnosis of CAA-ri was established with brain biopsy. Levels of anti-Aβ 42 antibody, Aβ 40, Aβ 42 and IL-8 in CSF were measured in the CAA-ri patient at 23 time points in the 8-month clinical course. These CSF samples were divided into 2 groups: those obtained before (n = 12) and those after (n = 11) oral corticosteroid therapy was started. We compared these levels between CSF samples obtained before and after therapy. The mean levels of anti-Aβ 42 antibody and IL-8 were significantly higher in CSF samples of the CAA-ri patient before oral corticosteroid therapy than those after therapy. A positive correlation was noted between levels of anti-Aβ 42 antibodies and IL-8 in CSF of this patient. There were no significant differences of mean levels of Aβ 40 and Aβ 42 between CSF samples obtained before and after oral corticosteroid therapy. It was possible that the autoinflammatory process with anti-Aβ 42 antibodies and IL-8 may have been involved in the pathogenesis of CAA-ri, and that corticosteroid therapy directly affected levels of anti-Aβ 42 antibody and IL-8. In summary, CAA-ri encephalopathy is a relapsing or progressive disorder and may be treatable by adequate immunosuppressive therapy. The anti-Aβ 42 antibody in CSF is a useful biological marker for therapeutic monitoring of CAA-ri.

Topics: Adrenal Cortex Hormones; Aged; Aged, 80 and over; Amyloid beta-Peptides; Antibodies; Biopsy; Brain; Cell Count; Cerebral Amyloid Angiopathy; Female; Humans; Inflammation; Interleukin-8; Magnetic Resonance Imaging; Peptide Fragments; Polymerase Chain Reaction

Cerebral amyloid angiopathy-related inflammation (CAA-ri) is characterized by vasogenic edema and multiple cortical/subcortical microbleeds, sharing several aspects with the recently defined amyloid-related imaging abnormalities (ARIA) reported in Alzheimer's disease (AD) passive immunization therapies. Herein, we investigated the role of anti-amyloid β (Aβ) autoantibodies in the acute and remission phases of CAA-ri.. We used a novel ultrasensitive technique on patients from a retrospective multicenter case-control study, and evaluated the anti-Aβ autoantibody concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis, and 25 control subjects. Levels of soluble Aβ40, Aβ42, tau, P-181 tau, and APOE genotype were also investigated.. During the acute phase of CAA-ri, anti-Aβ autoantibodies were specifically increased and directly correlated with Aβ mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble Aβ and axonal degeneration markers decreased in parallel.. Our data support the hypothesis that the pathogenesis of CAA-ri may be mediated by a selective autoimmune reaction against cerebrovascular Aβ, directly related to autoantibody concentration and soluble Aβ. The CSF dosage of anti-Aβ autoantibodies with the technique here described can thus be proposed as a valid alternative tool for the diagnosis of CAA-ri. Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-Aβ autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA.

Topics: Adult; Aged; Amyloid beta-Peptides; Apolipoproteins E; Autoantibodies; Brain; Case-Control Studies; Cerebral Amyloid Angiopathy; Female; Humans; Inflammation; Male; Middle Aged; Peptide Fragments; Phosphorylation; Retrospective Studies; Steroids; tau Proteins

Age-related macular degeneration (AMD) is the predominant cause of irreversible blindness in the elderly population. Despite intensive basic and clinical research, its pathogenesis remains unclear. However, evidence suggests that immunological and inflammatory factors contribute to the pathogenesis of AMD. A newly identified cytokine, IL-33, appears to be an important pro-inflammatory cytokine promoting tissue inflammation. In this study, IL-33 was increased through amyloid-beta(1-40) (Aβ(1-40)) stimulation and regulated inflammatory cytokines including IL-6, IL-8, IL-1β, and TNF-α secretion using different signaling pathways in retinal pigment epithelium (RPE) cells. Furthermore, ST2L, the important component of the IL-33 receptor, was significantly increased following recombinant human IL-33 stimulation in RPE cells. These findings suggest that IL-33-mediated inflammatory responses in RPE cells are involved in the pathogenesis of AMD. Greater understanding of the inflammatory effect of IL-33 and its role in RPE cells should aid the development of future clinical therapeutics and enable novel pharmacological approaches towards the prevention of AMD.

Topics: Amyloid beta-Peptides; Anthracenes; Butadienes; Cell Line; Humans; Imidazoles; Inflammation; Interleukin-1 Receptor-Like 1 Protein; Interleukin-1beta; Interleukin-33; Interleukin-6; Interleukin-8; Interleukins; JNK Mitogen-Activated Protein Kinases; Macular Degeneration; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-kappa B; Nitriles; Peptide Fragments; Pyridines; Receptors, Cell Surface; Retinal Pigment Epithelium; Sulfones; Tumor Necrosis Factor-alpha

Neuroinflammation is important in the pathogenesis and progression of Alzheimer disease (AD). Previously, we demonstrated that lipopolysaccharide (LPS)-induced neuroinflammation caused memory impairments. In the present study, we investigated the possible preventive effects of 4-O-methylhonokiol, a constituent of Magnolia officinalis, on memory deficiency caused by LPS, along with the underlying mechanisms.. We investigated whether 4-O-methylhonokiol (0.5 and 1 mg/kg in 0.05% ethanol) prevents memory dysfunction and amyloidogenesis on AD model mice by intraperitoneal LPS (250 μg/kg daily 7 times) injection. In addition, LPS-treated cultured astrocytes and microglial BV-2 cells were investigated for anti-neuroinflammatory and anti-amyloidogenic effect of 4-O-methylhonkiol (0.5, 1 and 2 μM).. Oral administration of 4-O-methylhonokiol ameliorated LPS-induced memory impairment in a dose-dependent manner. In addition, 4-O-methylhonokiol prevented the LPS-induced expression of inflammatory proteins; inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as activation of astrocytes (expression of glial fibrillary acidic protein; GFAP) in the brain. In in vitro study, we also found that 4-O-methylhonokiol suppressed the expression of iNOS and COX-2 as well as the production of reactive oxygen species, nitric oxide, prostaglandin E2, tumor necrosis factor-α, and interleukin-1β in the LPS-stimulated cultured astrocytes. 4-O-methylhonokiol also inhibited transcriptional and DNA binding activity of NF-κB via inhibition of IκB degradation as well as p50 and p65 translocation into nucleus of the brain and cultured astrocytes. Consistent with the inhibitory effect on neuroinflammation, 4-O-methylhonokiol inhibited LPS-induced Aβ1-42 generation, β- and γ-secretase activities, and expression of amyloid precursor protein (APP), BACE1 and C99 as well as activation of astrocytes and neuronal cell death in the brain, in cultured astrocytes and in microglial BV-2 cells.. These results suggest that 4-O-methylhonokiol inhibits LPS-induced amyloidogenesis via anti-inflammatory mechanisms. Thus, 4-O-methylhonokiol can be a useful agent against neuroinflammation-associated development or the progression of AD.

Topics: Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Analysis of Variance; Animals; Anti-Inflammatory Agents; Aspartic Acid Endopeptidases; Astrocytes; Avoidance Learning; Biphenyl Compounds; Brain; Cell Line, Transformed; Cyclooxygenase 2; Cytokines; Dinoprostone; Disease Models, Animal; Electrophoretic Mobility Shift Assay; Glial Fibrillary Acidic Protein; In Situ Nick-End Labeling; Inflammation; Lignans; Lipopolysaccharides; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred ICR; Microglia; NF-kappa B; Nitric Oxide; Peptide Fragments

Endogenously produced hydrogen sulfide (H(2)S) may have multiple functions in brain. An increasing number of studies have demonstrated its anti-inflammatory effects. In the present study, we investigated the effect of sodium hydrosulfide (NaHS, a H(2)S donor) on cognitive impairment and neuroinflammatory changes induced by injections of Amyloid-β(1-40) (Aβ(1-40)), and explored possible mechanisms of action.. We injected Aβ(1-40) into the hippocampus of rats to mimic rat model of Alzheimer's disease (AD). Morris water maze was used to detect the cognitive function. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was performed to detect neuronal apoptosis. Immunohistochemistry analyzed the response of glia. The expression of interleukin (IL)-1β and tumor necrosis factor (TNF)-α was measured by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). The expression of Aβ(1-40), phospho-p38 mitogen-activated protein kinase (MAPK), phospho-p65 Nuclear factor (NF)-κB, and phospho-c-Jun N-terminal Kinase (JNK) was analyzed by western blot.. We demonstrated that pretreatment with NaHS ameliorated learning and memory deficits in an Aβ(1-40) rat model of AD. NaHS treatment suppressed Aβ(1-40)-induced apoptosis in the CA1 subfield of the hippocampus. Moreover, the over-expression in IL-1β and TNF-α as well as the extensive astrogliosis and microgliosis in the hippocampus induced by Aβ(1-40) were significantly reduced following administration of NaHS. Concomitantly, treatment with NaHS alleviated the levels of p38 MAPK and p65 NF-κB phosphorylation but not JNK phosphorylation that occurred in the Aβ(1-40)-injected hippocampus.. These results indicate that NaHS could significantly ameliorate Aβ(1-40)-induced spatial learning and memory impairment, apoptosis, and neuroinflammation at least in part via the inhibition of p38 MAPK and p65 NF-κB activity, suggesting that administration of NaHS could provide a therapeutic approach for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Hippocampus; Hydrogen Sulfide; Inflammation; Male; Memory Disorders; Peptide Fragments; Random Allocation; Rats; Rats, Wistar; Spatial Behavior

Alzheimer's disease (AD) is characterized by amyloid-β peptide deposition, increased activated microglia, and progressive loss of neurons in the brain. Although Aβ₁₋₄₀ can elicit inflammation in microglia, the intracellular signaling events mediating these effects are poorly defined. Here we show that cell-free supernatant from Aβ₁₋₄₀-treated THP-1 monocytes induced cytotoxicity towards neuroblastoma SK-N-SH cells. Exposure of THP-1 monocytes to Aβ₁₋₄₀ leads to increased tyrosine phosphorylation and extracellular signaling-regulated kinase (ERK) and increased levels of inflammatory cytokines (IL-1β, IL-8, and TNF-α) in the supernatant of THP-1 monocytes. Pretreatment of THP-1 monocytes with either a protein tyrosine kinase (PTK) inhibitor or an ERK inhibitor protects SK-N-SH cells from the cytotoxic effect of conditional supernatant from Aβ₁₋₄₀-treated THP-1 monocytes. Aβ₁₋₄₀-treated THP-1 monocytes also lead to upregulation of cyclooxygenase-2 and iNOS expression and increased of nitric oxide production. These results suggest that Aβ₁₋₄₀-induced activation of PTK/MEK/ERK pathway in THP-1 monocytes leads to the release of inflammatory factors that are toxic to SK-N-SH cells and might contribute to the onset of AD.

Topics: Amyloid beta-Peptides; Blotting, Western; Cell Line; Cytotoxicity, Immunologic; Enzyme Activation; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Humans; Inflammation; MAP Kinase Signaling System; Microscopy, Electron, Transmission; Monocytes; Neuroblastoma; Neurons; Peptide Fragments

Alzheimer's disease (AD) is a neurodegenerative disorder, which depicts features of chronic inflammatory conditions resulting in cellular death and has limited therapeutic options. We aimed to explore the effect of a curcuminoid mixture and its individual components on inflammatory and apoptotic genes expression in AD using an Aβ+ibotenic acid-infused rat model. After 5 days of treatment with demethoxycurcumin, hippocampal IL-1β levels were decreased to 118.54 ± 47.48 and 136.67 ± 31.96% respectively at 30 and 10mg/kg, compared with the amyloid treated group (373.99 ± 15.28%). After 5 days of treatment, the curcuminoid mixture and demethoxycurcumin effectively decreased GFAP levels in the hippocampus. When studied for their effect on apoptotic genes expression, the curcuminoid mixture and bisdemethoxycurcumin effectively decreased caspase-3 level in the hippocampus after 20 days of treatment, where bisdemethoxycurcumin showed a maximal rescuing effect (92.35 ± 3.07%) at 3mg/kg. The curcuminoid mixture at 30 mg/kg decreased hippocampal FasL level to 70.56 ± 3.36% after 5 days of treatment and 19.01 ± 2.03% after 20 days. In the case of Fas receptor levels, demethoxycurcumin decreased levels after 5 days of treatment with all three doses showing a maximal effect (189.76 ± 15.01%) at 10mg/kg. Each compound was effective after 20 days in reducing Fas receptor levels in the hippocampus. This study revealed the important effect of curcuminoids on genes expression, showing that, each component of the curcuminoid mixture distinctly affects gene expression, thus highlighting the therapeutic potential of curcuminoids in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Curcumin; Cyclooxygenase 2; Disease Models, Animal; Excitatory Amino Acid Agonists; Fas Ligand Protein; fas Receptor; Frontal Lobe; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Hippocampus; Ibotenic Acid; Inflammation; Interleukin-1beta; Male; Peptide Fragments; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Time Factors

Amyloid precursor protein (APP) is a ubiquitously expressed cell surface protein reported to be involved in mediating cell-cell or cell-matrix interactions. Prior work has demonstrated that APP co-localizes with beta1 integrin in different cell types.. In an effort to determine the function of APP on monocytic lineage cells, in particular, the human monocyte cell line, THP-1, was used to assess the role of APP during adhesion to the extracelluar matrix component type I collagen.. Pull-down assays demonstrated that THP-1 adhesion to collagen stimulated a tyrosine kinase-associated signaling response which included subsequent phosphorylation of p38 MAP kinase and increased association of APP with alpha2beta1 integrin, specifically. In addition, cell adhesion was dependent upon APP expression since APP siRNA knockdown attenuated THP-1 adhesion to collagen compared to mock transfected controls. One consequence of the tyrosine kinase-dependent signaling response was increased secretion of interleukin-1beta (IL-1beta) and Abeta1-40 but not the Abeta1-42 fragment of APP. Increased secretion of IL-1beta was dependent upon p38 MAP kinase activity while Abeta1-40 secretion required Src family kinase activity since the specific p38 inhibitor, SB202190, and the Src family kinase inhibitor, PP2, attenuated IL-1beta and Abeta1-40 secretion, respectively.. These data demonstrate that APP is involved in classic integrin-dependent tyrosine kinase-associated adhesion and activation of peripheral monocytic cells. Moreover, divergent APP-dependent signaling is required for increased secretion of both IL-1beta and Abeta1-40 as a component of the adhesion-dependent change in phenotype. This suggests that APP may have a broad role in not only mediating cell-matrix adhesion but also in the function of peripheral immune cells.

Topics: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Blotting, Western; Brain Chemistry; Cell Adhesion; Cell Line; Cerebrovascular Circulation; Collagen Type I; Enzyme-Linked Immunosorbent Assay; Humans; Immunoprecipitation; Inflammation; Interleukin-1beta; p38 Mitogen-Activated Protein Kinases; Peptide Fragments; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; RNA, Small Interfering; Signal Transduction; src-Family Kinases; Transfection

To investigate the effect and mechanism of meloxicam on the inflammatory reaction induced by beta amyloid protein (AB) in Alzheimer's disease (AD) rats.. The rat model was established by microinjection of Abeta(1-40) into hippocampus. The expression of NF-kappaB p65 and glial fibrillary acidic protein (GFAP) in hippocampus were detected by immunohistochemistry. The content of GFAP in cortex was tested by Western-blot. The content of TNF-alpha in cortex was tested by ELISA. The expression of IL-1beta mRNA was tested by RT-PCR.. The expression of NF-kappaB p65, GFAP and TNF-alpha as well as IL-1beta mRNA were decreased by meloxicam.. Meloxicam can reduce the proliferation of astrocyte by decreasing the expression of GFAP in AD model rat's hippocampus and cortex. And the depression of NF-kappaB p65 may significantly decrease the expression of TNF-alpha1 and IL-1beta to lessen the inflammatory reaction in cerebral tissue.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebral Cortex; Glial Fibrillary Acidic Protein; Inflammation; Interleukin-1beta; Male; Meloxicam; Peptide Fragments; Rats; Rats, Sprague-Dawley; Thiazines; Thiazoles; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Alzheimer's disease is characterized by accumulation and deposition of Aβ peptides in the brain. Aβ deposition generates reactive-oxygen species (ROS), which are involved in Alzheimer's inflammatory and neurodegenerative pathology. We have previously observed that, in Alzheimer's disease brain, ABCG2 is up-regulated and AP-1 is activated, but NF-κB is not activated. In the present study, we examine the roles and mechanism of ABCG2 on ROS generation, inflammatory gene expression and signaling, heme homeostasis and Aβ production in cell models and on inflammatory signaling and Aβ deposition in Abcg2-knockout and wild-type mice. Our results show that ABCG2 plays a protective role against oxidative stress by decreasing ROS generation, enhancing antioxidant capacity, regulating heme level, and inhibiting inflammatory response in cell models. ABCG2 inhibits NF-κB activation but has less effect on AP-1 activation induced by ROS. This results in inhibition of interleukin-8 and growth-related oncogene (GRO) expression induced by ROS via NF-κB pathway. Abcg2 deficiency increased Aβ deposition and NF-κB activation in the brains of Abcg2-knockout mice compared with controls. These findings suggest that ABCG2 may relieve oxidative stress and inflammatory response via inhibiting NF-κB signaling pathway in cell models and brain tissues and thus may play a potential protective role in Alzheimer's neuroinflammatory response.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Brain; Cell Line; Cell Line, Tumor; Cell Survival; Chemokine CXCL1; Chemokine CXCL2; Hemin; Humans; Hydrogen Peroxide; Inflammation; Interleukin-8; Mice; Mice, Knockout; Neoplasm Proteins; NF-kappa B; Peptide Fragments; Reactive Oxygen Species; tert-Butylhydroperoxide

The hallmarks of Alzheimer's disease include the deposition of beta-amyloid (Abeta), neuroinflammation, and cognitive deficits. The accumulation of activated glial cells in cognitive-related areas is critical for these alterations, although little is known about the mechanisms driving this event. Herein we used macrophage inflammatory protein-1alpha (MIP-1alpha(-/-))- or CC-chemokine receptor 5 (CCR5(-/-))-deficient mice to address the role played by chemokines in molecular and behavioral alterations induced by Abeta(1-40). Abeta(1-40) induced a time-dependent increase of MIP-1alpha mRNA followed by accumulation of activated glial cells in the hippocampus of wild-type mice. MIP-1alpha(-/-) and CCR5(-/-) mice displayed reduced astrocytosis and microgliosis in the hippocampus after Abeta(1-40) administration that was associated with decreased expression of cyclooxygenase-2 and inducible nitric oxide synthase, as well as reduced activation of nuclear factor-kappaB, activator protein-1 and cyclic AMP response element-binding protein. Furthermore, MIP-1alpha(-/-) and CCR5(-/-) macrophages showed impaired chemotaxis in vitro, although cytokine production in response to Abeta(1-40) was unaffected. Notably, the cognitive deficits and synaptic dysfunction induced by Abeta(1-40) were also attenuated in MIP-1alpha(-/-) and CCR5(-/-) mice. Collectively, these results indicate that the MIP-1alpha/CCR5 signaling pathway is critical for the accumulation of activated glial cells in the hippocampus and, therefore, for the inflammation and cognitive failure induced by Abeta(1-40). Our data suggest MIP-1alpha and CCR5 as potential therapeutic targets for Alzheimer's disease treatment.

Topics: Amyloid beta-Peptides; Animals; Cell Movement; Chemokine CCL3; Cognition Disorders; Cyclooxygenase 2; Gene Deletion; Hippocampus; Humans; Inflammation; Male; Memory; Mice; Mice, Inbred C57BL; Nervous System; Neuroglia; Nitric Oxide Synthase Type II; Peptide Fragments; Receptors, CCR5; Signal Transduction; Synapses; Transcription Factors; Up-Regulation

Increased deposition of amyloid beta (Abeta) is characteristic for normal aging and human immunodeficiency virus-1 (HIV-1)-associated alterations of the central nervous system. In addition, both Abeta and HIV-1 are known to induce cellular oxidative stress and disruption of the blood-brain barrier (BBB). Therefore, we hypothesize that Abeta and HIV-1 protein Tat can potentiate their proinflammatory effects at the brain endothelium level. To address this hypothesis, we studied promoter activity of three proinflammatory genes in an in vitro BBB model of human brain microvascular endothelial cells (HBMEC) cocultured with a human astrocyte cell line producing Tat (SVGA-Tat cells) and exposed to Abeta. Treatment of HBMEC with Abeta(1-40) in the presence of SVGA-Tat cells resulted in a significant up-regulation of E-selectin, CC chemokine ligand-2, and interleukin-6 promoter activities and protein levels compared with the individual effects of Abeta or Tat. In addition, Abeta markedly amplified E-selectin promoter activity in HBMEC cocultured with HIV-1-infected Jurkat T cells. Simvastatin, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, effectively blocked proinflammatory reactions induced by Abeta in cocultures with SVGA-Tat cells or with HIV-1-infected Jurkat cells. The present study indicates that a combined exposure to Abeta and Tat or HIV-1 can synergistically potentiate the expression of inflammatory genes in brain endothelial cells. In addition, simvastatin may provide a beneficial influence by reducing these effects at the BBB level.

Topics: Amyloid beta-Peptides; Anticholesteremic Agents; Astrocytes; Brain; Cell Line, Transformed; Cytoprotection; Endothelial Cells; Gene Expression Regulation; HIV-1; Humans; Inflammation; Inflammation Mediators; Jurkat Cells; Peptide Fragments; Promoter Regions, Genetic; Selectins; Simvastatin; tat Gene Products, Human Immunodeficiency Virus; Transcriptional Activation

The interaction of endogenous and exogenous stimulators of innate immunity was examined in primary cultures of mouse microglial cells and macrophages after application of defined Toll-like receptor (TLR) agonists [lipopolysaccharide (LPS) (TLR4), the synthetic lipopeptide Pam3Cys-Ser-Lys4 (Pam3Cys) (TLR2) and single-stranded unmethylated CpG-DNA (CpG) (TLR9)] alone and in combination with amyloid beta peptide (Abeta) 1-40. Abeta1-40 stimulated microglial cells and macrophages primed by interferon-gamma in a dose-dependent manner. Co-administration of Abeta1-40 with LPS or Pam3Cys led to an additive release of nitric oxide (NO) and tumour necrosis factor alpha (TNF-alpha). This may be one reason for the clinical deterioration frequently observed in patients with Alzheimer's disease during infections. In contrast, co-application of Abeta1-40 with CpG led to a substantial decrease of NO and TNF-alpha release compared with stimulation with CpG alone. Abeta1-40 and CpG did not co-localize within the same subcellular compartment, making a direct physicochemical interaction as the cause of the observed antagonism very unlikely. This suggests that not all TLR agonists enhance the stimulatory effect of A beta on innate immunity.

Topics: Amyloid beta-Peptides; Analysis of Variance; Animals; Animals, Newborn; Blotting, Western; Brain; Cell Survival; Cells, Cultured; Cytokines; DNA-Binding Proteins; DNA, Bacterial; Dose-Response Relationship, Drug; Drug Interactions; Enzyme-Linked Immunosorbent Assay; Immunohistochemistry; Inflammation; Lectins; Lipopolysaccharides; Lipoproteins; Macrophages; Mice; Mice, Inbred C57BL; Microglia; Microscopy, Confocal; Nitrites; Peptide Fragments; Receptors, Cell Surface; Receptors, Immunologic; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptor 9

beta-Amyloid (Abeta) plaques are characteristic hallmarks of Alzheimer's disease (AD). In AD, it has been suggested that activation of microglial cells might be the link between Abeta deposition and neuronal degeneration. Activated microglia are associated with senile plaques and produce free radicals and inflammatory cytokines. However, it is still not clear whether Abeta needs a prestimulated environment to exert its proinflammatory potential. Advanced glycation endproducts (AGEs), protein-bound oxidation products of sugars, have been shown to accumulate in senile plaques and could induce a silent but chronic inflammation in the AD brain. We tested whether Abeta acts as an amplifier of a submaximal proinflammatory response initiated by exposure to chicken egg albumin-AGE, lipopolysaccharide or interferon-gamma. Synthetic Abeta was used to produce three different samples (Abeta-fibrilar; Abeta-aggregated; Abeta-AGE), which were characterized for beta-sheeted fibrils by the thioflavin-T test and electron microscopy. As markers of microglial activation, nitric oxide, interleukin-6, macrophage-colony stimulation factor and tumour necrosis factor-alpha production was measured. All three Abeta samples alone could not induce a detectable microglial response. The combination of Abeta preparations, however, with the coinducers provoked a strong microglial response, whereby Abeta-AGE and fibrilar Abeta were more potent inflammatory signals than aggregated Abeta. Thus, Abeta in senile plaques can amplify microglial activation by a coexisting submaximal inflammatory stimulus. Hence, anti-inflammatory therapeutics could either target the primary proinflammatory signal (e.g. by limiting AGE-formation by AGE inhibitors or cross-link breakers) or the amplifyer Abeta (e.g. by limiting Abeta production by beta- or gamma-secretase inhibitors).

Topics: Amyloid; Amyloid beta-Peptides; Animals; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Drug Synergism; Glycation End Products, Advanced; Inflammation; Interferon-gamma; Interleukin-6; Lipopolysaccharides; Macrophage Colony-Stimulating Factor; Mice; Microglia; Microscopy, Electron; Nitric Oxide; Peptide Biosynthesis; Peptide Fragments; Plaque, Amyloid; Tumor Necrosis Factor-alpha

Reactive microglia associated with the beta-amyloid plaques in Alzheimer's disease (AD) brains initiate a sequence of inflammatory events integral to the disease process. We have observed that fibrillar beta-amyloid peptides activate a tyrosine kinase-based signaling response in primary mouse microglia and the human monocytic cell line, THP-1, resulting in production of neurotoxic secretory products, proinflammatory cytokines, and reactive oxygen species. We report that most of the amyloid-induced tyrosine kinase activity was stimulated after activation of Src family members such as Lyn. However, transduction of the signaling response required for increased production of the cytokines TNFalpha and IL1-beta was mediated by the nonreceptor tyrosine kinase, Syk. Additionally, beta-amyloid stimulated an NFkappaB-dependent pathway in parallel that was required for cytokine production. Importantly, TNFalpha generated by the monocytes and microglia was responsible for the majority of the neuorotoxic activity secreted by these cells after beta-amyloid stimulation but must act in concert with other factors elaborated by microglia to elicit neuronal death. Moreover, we observed that the neuronal loss was apoptotic in nature and involved increased neuronal expression of inducible nitric oxide synthase and subsequent peroxynitrite production. Selective inhibitors of inducible nitric oxide synthase effectively protected cells from toxicity associated with the microglial and monocytic secretory products. This study demonstrates a functional linkage between beta-amyloid-dependent activation of microglia and several characteristic markers of neuronal death occurring in Alzheimer's disease brains.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Cells, Cultured; Contraindications; Enzyme Precursors; Humans; Inflammation; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Microglia; Monocytes; Neurons; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peptide Fragments; Protein-Tyrosine Kinases; Signal Transduction; src-Family Kinases; Syk Kinase; Transcription Factors; Tumor Necrosis Factor-alpha

The murine cell line MMGT-16 is of microglial origin and capable of releasing immunoinflammatory cytokines. When stimulated by the proinflammatory stimulus lipopolysaccharide (LPS), MMGT-16 cells secrete large amounts of prostaglandin E(2) (PGE(2)). This PGE(2) production is nearly abolished if amyloid beta-peptide (Abeta (1-40)) is present in the incubation medium. In addition, Abeta (1-40) inhibits cyclooxygenase-2 (COX-2) induction by LPS. Since these effects are not reproduced by the reverse control Abeta (40-1), these results suggest a novel, intriguing modulatory role for amyloid beta peptide in the inflammatory response of microglial cells.

Topics: Amyloid beta-Peptides; Animals; Blotting, Western; Cell Line; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Enzyme Induction; Inflammation; Isoenzymes; Lipopolysaccharides; Membrane Proteins; Mice; Microglia; Peptide Fragments; Prostaglandin-Endoperoxide Synthases; Radioimmunoassay

Alzheimer's disease (AD) is characterized by the extracellular deposition of beta-amyloid fibrils within the brain and the subsequent association and phenotypic activation of microglial cells associated with the amyloid plaque. The activated microglia mount a complex local proinflammatory response with the secretion of a diverse range of inflammatory products. Nonsteroidal anti-inflammatory drugs (NSAIDs) are efficacious in reducing the incidence and risk of AD and significantly delaying disease progression. A recently appreciated target of NSAIDs is the ligand-activated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). PPARgamma is a DNA-binding transcription factor whose transcriptional regulatory actions are activated after agonist binding. We report that NSAIDs, drugs of the thiazolidinedione class, and the natural ligand prostaglandin J2 act as agonists for PPARgamma and inhibit the beta-amyloid-stimulated secretion of proinflammatory products by microglia and monocytes responsible for neurotoxicity and astrocyte activation. The activation of PPARgamma also arrested the differentiation of monocytes into activated macrophages. PPARgamma agonists were shown to inhibit the beta-amyloid-stimulated expression of the cytokine genes interleukin-6 and tumor necrosis factor alpha. Furthermore, PPARgamma agonists inhibited the expression of cyclooxygenase-2. These data provide direct evidence that PPARgamma plays a critical role in regulating the inflammatory responses of microglia and monocytes to beta-amyloid. We argue that the efficacy of NSAIDs in the treatment of AD may be a consequence of their actions on PPARgamma rather than on their canonical targets the cyclooxygenases. Importantly, the efficacy of these agents in inhibiting a broad range of inflammatory responses suggests PPARgamma agonists may provide a novel therapeutic approach to AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal; Astrocytes; Brain; Cell Differentiation; Chromans; Cyclooxygenase 2; Dinoprost; Genes, Reporter; Humans; Inflammation; Interleukin-6; Isoenzymes; Membrane Proteins; Mice; Mice, Inbred C57BL; Microbodies; Microglia; Monocytes; Peptide Fragments; Prostaglandin-Endoperoxide Synthases; Receptors, Cytoplasmic and Nuclear; Recombinant Proteins; Tetradecanoylphorbol Acetate; Thiazoles; Thiazolidinediones; Transcription Factors; Transfection; Troglitazone; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Mounting evidence from in vitro and in vivo studies in transgenic mice overproducing beta-amyloid peptides (A beta) suggests that A beta can induce vasoconstriction and decrease cerebral blood flow. In this report, we describe the vasoactive properties of A beta, in particular the enhancement of endothelin-1-induced vasoconstriction and A beta's induction of a long-lasting vasoconstrictive event. Furthermore, we show that low doses (as low as 50 nM) of freshly solubilized A beta similar to those observed in the plasma of patients suffering from Alzheimer's disease are vasoactive. By using various inhibitors and activators of the phospholipase A2 (PLA2)/arachidonic acid (AA) cascade, we demonstrate that A beta vasoactivity is dependent on activation of this intracellular signaling pathway, resulting in stimulation of downstream cyclooxygenase-2 and 5-lipoxygenase, which mediate production of proinflammatory eicosanoids. Taken together, our data show that A beta directly activates an intracellular proinflammatory pathway, which is responsible for its vasoactive properties.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Animals; Aorta; Cyclooxygenase Inhibitors; Endothelin-1; Humans; In Vitro Techniques; Inflammation; Lipoxygenase Inhibitors; Male; Mice; Mice, Transgenic; Muscle, Smooth, Vascular; Peptide Fragments; Rats; Rats, Sprague-Dawley; Signal Transduction; Vasoconstriction; Vasodilation

This in vivo animal model of vascular inflammatory reaction facilitates morphologic and hemodynamic analyses of leukocyte-endothelial interaction and can be monitored by video microscopy and electron microscopy. The model has served as a rapid means to explore the deleterious vascular actions and inflammatory response to the cytokines tumor necrosis factor, interleukin-1 and amyloid-beta, as well as the protective effects of superoxide dismutase, estrogen, and cytokine antagonists.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Arterioles; Carrier Proteins; Disease Models, Animal; Endothelium, Vascular; Estrogens; Hemodynamics; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Leukocytes; Male; Microscopy, Electron; Microscopy, Video; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Sialoglycoproteins; Superoxide Dismutase; Tumor Necrosis Factor Decoy Receptors; Tumor Necrosis Factor-alpha

Topics: Amyloid beta-Peptides; Animals; Aorta; Cyclic GMP; Dipyridamole; Endothelin-1; In Vitro Techniques; Inflammation; Leukotriene B4; Microglia; Muscle, Smooth, Vascular; Nitroprusside; Peptide Fragments; Rats; Vasoconstriction

A chronic inflammatory response possibly mediated by amyloid-beta (A beta) is believed to be a major factor in the pathology of Alzheimer's disease (AD). Recently, we demonstrated that in vivo administration of A beta produces an inflammatory response and vascular disruption as seen in the brains of AD patients. In an inflammatory response, leukocyte activation and extravasation involves cytokine production. Previous studies have indicated that immune interactions exist between the central nervous system and the peripheral immune mechanisms in AD. Increased levels of interleukin-1 beta (IL-1 beta) have been detected in brain tissue, cerebrospinal fluid, and blood/serum from AD patients. In addition, A beta stimulated the production of tumor necrosis factor-alpha (TNF-alpha) in brain astrocytes and murine monocytes. Using an animal model we investigated the role of the cytokines, TNF-alpha and IL-1 beta, in the A beta-induced inflammatory response. Adult male rats were perfused via an intra-aortic cannula with either A beta alone, interleukin-1 receptor antagonist (IL-1 ra) plus A beta, tumor necrosis factor-binding protein (TNF-bp) plus A beta or sterile saline. Serum analysis for TNF-alpha, IL-1 beta, A beta and NO showed a significant increase in TNF-alpha and A beta but not in IL-1 beta or NO after the injection of A beta. Control values for serum A beta averaged 1.6 ng/ml and in rats injected with A beta, 99.6% of this peptide was removed from the blood within 30 min. The mesenteric arterioles and venules were video recorded for 1-2 h and then processed for electron microscopy (EM). In rats given A beta alone there was extensive vascular disruption, including endothelial and smooth muscle damage with leukocyte adhesion and migration. Animals receiving either IL-1 ra or TNF-bp before A beta showed no in vivo leukocyte extravasation or vascular damage under EM. Therefore, the cytokines TNF-alpha and IL-1 beta seem to mediate the vascular disruption and inflammatory response initiated by A beta. Antagonism of these pro-inflammatory cytokines may offer new avenues for AD therapy.

Topics: Amyloid beta-Peptides; Animals; Carrier Proteins; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Male; Mesenteric Arteries; Microscopy, Electron; Nitric Oxide; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Sialoglycoproteins; Tumor Necrosis Factor Decoy Receptors; Tumor Necrosis Factor-alpha