salicylates and Alzheimer-Disease

Chemical and physical properties of nanobio interface substantially affect the conformational transitions of adjacent biomolecules. Previous studies have reported the chiral effect and charge effect of nanobio interface on the misfolding, aggregation, and fibrillation of amyloid protein. However, the isomeric effect of nanobio interface on protein/peptides amyloidosis is still unclear. Here, three isomeric nanobio interfaces were designed and fabricated based on the same sized gold nanoclusters (AuNCs) modified with 4-mercaptobenzoic acid (

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Benzoates; Gold; Humans; Isomerism; Metal Nanoparticles; Peptide Fragments; Protein Aggregates; Protein Folding; Salicylates; Sulfhydryl Compounds

Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.

Topics: Acetylation; Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Brain Injuries, Traumatic; Cell Line; Diflunisal; Female; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Humans; Male; Mice; Mice, Inbred C57BL; Neurons; Neuroprotection; p300-CBP Transcription Factors; Salicylates; Sirtuin 1; tau Proteins

Topics: Acetylation; Alzheimer Disease; Animals; Humans; Methylene Blue; Mice; Salicylates; Severity of Illness Index; tau Proteins

Alzheimer's disease (AD), a leading cause of dementia, becomes a serious health issue for individuals and society around the world. AD is a neurodegenerative disease characterized by the deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles (NFT) and the loss of large numbers of neurons. To date, there is no effective treatment for AD, and thus, to enhance neurogenesis in the AD brain may be a therapeutic strategy. RAS signaling pathway involves in synaptic plasticity and memory formation, which is overexpressed in brains with AD. This study used Aβ. The results demonstrated that FTS could prevent Aβ. In conclusion, these findings suggest that FTS as a RAS inhibitor could be a potential therapeutic agent for the treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Doublecortin Protein; Extracellular Signal-Regulated MAP Kinases; Farnesol; Injections, Intraperitoneal; Male; MAP Kinase Signaling System; Maze Learning; Mice; Mice, Inbred ICR; Molecular Structure; Neuroprotective Agents; ras Proteins; Salicylates; Stereoisomerism

Alzheimer's disease (AD) is characterized by progressive decline of cognition and associated neuropsychiatric signs including weight loss, anxiety, depression, agitation, and aggression, which is particularly pronounced in the female gender. Previously, we have shown that a novel ionic co-crystal of lithium salicylate proline (LISPRO) is an improved lithium formulation compared to the carbonate or salicylate form of lithium in terms of safety and efficacy in reducing AD pathology in Alzheimer's mice. The current study is designed to compare the prophylactic effects of LISPRO, lithium carbonate (LC), and lithium salicylate (LS) on cognitive and noncognitive impairments in female transgenic APPswe/PS1dE9 AD mice. Female APPswe/PS1dE9 mice at 4 months of age were orally treated with low-dose LISPRO, LS, or LC for 9 months at 2.25 mmol lithium/kg/day followed by determination of body weight, growth of internal organs, and cognitive and noncognitive behavior. No significant differences in body or internal organ weight, anxiety or locomotor activity were found between lithium treated and untreated APPswe/PS1dE9 cohorts. LISPRO, LC, and LS prevented spatial cognitive decline, as determined by Morris water maze and depression as determined by tail suspension test. In addition, LISPRO treatment was superior in preventing associative memory decline determined by contextual fear conditioning and reducing irritability determined by touch escape test in comparison with LC and LS. In conclusion, low-dose LISPRO, LC, and LS treatment prevent spatial cognitive decline and depression-like behavior, while LISPRO prevented hippocampal-dependent associative memory decline and irritability in APPswe/PS1dE9 mice.

Topics: Alzheimer Disease; Animals; Behavior; Body Weight; Conditioning, Psychological; Fear; Female; Hindlimb Suspension; Lithium Carbonate; Lithium Compounds; Locomotion; Maze Learning; Memory; Mice; Mice, Transgenic; Motor Activity; Proline; Salicylates; Spatial Memory

A series of salicyladimine derivatives were designed, synthesized and evaluated as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some derivatives possessed significant inhibitory activities against amyloid-β (Aβ) aggregation and human monoamine oxidase B (hMAO-B) as well as remarkable antioxidant effects and low cell toxicity. The optimal compound, 5, exhibited excellent potency for inhibition of self-induced Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Survival; Dose-Response Relationship, Drug; Drug Design; Humans; Hydrogen Peroxide; Imines; Ligands; Lipopolysaccharides; Mice; Microglia; Molecular Docking Simulation; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; PC12 Cells; Peptide Fragments; Protein Aggregates; Rats; Salicylates; Structure-Activity Relationship

Chikungunya virus (CHIKV) has been spreading rapidly, with over one million confirmed or suspected cases in the Americas since late 2013. Infection with CHIKV causes devastating arthritic and arthralgic symptoms. Currently, there is no therapy to treat this disease, and the only medications focus on relief of symptoms. Recently, protein kinase C (PKC) modulators have been reported to inhibit CHIKV-induced cell death in cell assays. The salicylate-derived bryostatin analogues described here are structurally simplified PKC modulators that are more synthetically accessible than the natural product bryostatin 1, a PKC modulator and clinical lead for the treatment of cancer, Alzheimer's disease, and HIV eradication. Evaluation of the anti-CHIKV activity of these salicylate-derived bryostatin analogues in cell culture indicates that they are among the most potent cell-protective agents reported to date. Given that they are more accessible and significantly more active than the parent natural product, they represent new therapeutic leads for controlling CHIKV infection. Significantly, these analogues also provide evidence for the involvement of a PKC-independent pathway. This adds a fundamentally distinct aspect to the importance or involvement of PKC modulation in inhibition of chikungunya virus replication, a topic of recent and growing interest.

Topics: Alzheimer Disease; Biological Products; Bryostatins; Cell Death; Chikungunya virus; Humans; Molecular Structure; Protein Kinase C; Salicylates; Virus Replication

Pharmacological manipulation of tau protein in Alzheimer's disease included microtubule-stabilizing agents, tau protein kinase inhibitors, tau aggregation inhibitors, active and passive immunotherapies and, more recently, inhibitors of tau acetylation. Animal studies have shown that both active and passive approaches can remove tau pathology and, in some cases, improve cognitive function. Two active vaccines targeting either nonphosphorylated (AAD-vac1) and phosphorylated tau (ACI-35) have entered Phase I testing. Notwithstanding, the recent discontinuation of the monoclonal antibody RG7345 for Alzheimer's disease, two other antitau antibodies, BMS-986168 and C2N-8E12, are also currently in Phase I testing for progressive supranuclear palsy. After the recent impressive results in animal studies obtained by salsalate, the dimer of salicylic acid, inhibitors of tau acetylation are being actively pursued.

Topics: Acetylation; Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Clinical Trials as Topic; Cognition; Disease Models, Animal; Humans; Immunization, Passive; Immunotherapy, Active; Microtubules; Salicylates; tau Proteins; Vaccines

Topics: Aged; Alzheimer Disease; Brain Injuries; Hematoma, Subdural; Humans; Male; Medication Errors; Prescription Drug Misuse; Salicylates

Intracellular accumulation of the abnormally modified tau is hallmark pathology of Alzheimer's disease (AD), but the mechanism leading to tau aggregation is not fully characterized. Here, we studied the effects of tau SUMOylation on its phosphorylation, ubiquitination, and degradation. We show that tau SUMOylation induces tau hyperphosphorylation at multiple AD-associated sites, whereas site-specific mutagenesis of tau at K340R (the SUMOylation site) or simultaneous inhibition of tau SUMOylation by ginkgolic acid abolishes the effect of small ubiquitin-like modifier protein 1 (SUMO-1). Conversely, tau hyperphosphorylation promotes its SUMOylation; the latter in turn inhibits tau degradation with reduction of solubility and ubiquitination of tau proteins. Furthermore, the enhanced SUMO-immunoreactivity, costained with the hyperphosphorylated tau, is detected in cerebral cortex of the AD brains, and β-amyloid exposure of rat primary hippocampal neurons induces a dose-dependent SUMOylation of the hyperphosphorylated tau. Our findings suggest that tau SUMOylation reciprocally stimulates its phosphorylation and inhibits the ubiquitination-mediated tau degradation, which provides a new insight into the AD-like tau accumulation.

Topics: Alzheimer Disease; Amino Acid Substitution; Amyloid beta-Peptides; Androstadienes; Animals; Cerebral Cortex; Female; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; HEK293 Cells; Hippocampus; Humans; Indoles; Male; Maleimides; Middle Aged; Mutagenesis, Site-Directed; Mutation, Missense; Nerve Tissue Proteins; Peptide Fragments; Phosphorylation; Point Mutation; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Proteolysis; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Salicylates; Solubility; SUMO-1 Protein; Sumoylation; tau Proteins; Ubiquitination; Wortmannin

Sporadic Alzheimer's disease is an age-related neurological and psychiatric disorder characterized by impaired energy metabolism. Oxidative stress and neuroinflammation have been implicated in pathophysiology of sporadic type of dementia. The central streptozotocin administration induces behavioral and biochemical alterations resembling those in sporadic type of Alzheimer's patients. The present study was designed to investigate the effects of chronic pretreatment with cyclooxygenase-1 or cyclooxygenase-2 or cyclooxygenase-3 selective inhibitors on cognitive dysfunction and oxidative stress markers in intracerebroventricular streptozotocin-treated rats. Chronic treatment with valeryl salicylate (5 and 10 mg/kg, i.p.) and etoricoxib (5 and 10 mg/kg, i.p.) on a daily basis for a period of 21 days, beginning 1 h prior to first intracerebroventricular streptozotocin injection, significantly improved streptozotocin-induced cognitive impairment. However, phenacetin (20 and 40 mg/kg, i.p.) failed to restore the cognitive performances of streptozotocin-treated rats. Besides, improving cognitive dysfunction, chronic administration of highly selective cyclooxygenase-1 and/or cyclooxygenase-2 inhibitors (valeryl salicylate and etoricoxib, respectively), but not cyclooxygenase-3 inhibitor (phenacetin), significantly reduced elevated malondialdehyde, nitrite levels, and restored reduced glutathione and superoxide dismutase levels. Furthermore, cyclooxygenase-1 and/or cyclooxygenase-2 inhibitors significantly increased the survival of pyramidal neurons. In summary, we demonstrate for the first time that both cyclooxygenase-1 and cyclooxygenase-2 isoforms, but not cyclooxygenase-3, are involved in the progression of neuronal damage in intracerebroventricular streptozotocin-treated rats.

Topics: Alzheimer Disease; Animals; Antibiotics, Antineoplastic; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Etoricoxib; Injections, Intraventricular; Lipid Peroxidation; Male; Neuroprotective Agents; Pyridines; Rats; Rats, Wistar; Salicylates; Streptozocin; Sulfones

Complement plays a vital role in both the innate and adaptive immune systems. It recognizes a target, opsonizes it, generates anaphylatoxins, and directly kills cells through the membrane attack complex (MAC). This final function, which assembles C5b-9(n) on viable cell surfaces, can kill host cells through bystander lysis. Here we identify for the first time compounds that can inhibit bystander lysis while not interfering with the other essential functions of complement. We show that aurin tricarboxylic acid (ATA), aurin quadracarboxylic acid (AQA), and aurin hexacarboxylic acid (AHA), block the addition of C9 to C5b-8 so that the MAC cannot form. These molecules inhibit hemolysis of human, rat, and mouse red cells with a half maximal inhibitory concentration (IC(50)) in the nanomolar range. When given orally to Alzheimer disease type B6SJL-Tg mice, they inhibit MAC formation in serum and improve memory retention. On autopsy, they show no evidence of harm to any organ. Aurin tricarboxylic acid, aurin quadracarboxylic acid, and aurin hexacarboxylic acid may be effective therapeutic agents in Alzheimer disease and other degenerative disorders where self damage from the MAC occurs.

Topics: Alzheimer Disease; Animals; Aurintricarboxylic Acid; Bystander Effect; Complement System Proteins; Hemolysis; Humans; Memory; Mice; Mice, Transgenic; Rats; Salicylates

Alzheimer's disease is a neurodegenerative disorder that is characterized by the accumulation of senile plaques containing amyloid β (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein in the brain. Oxidative stress has been proposed to mediate Aβ-induced neurotoxicity. In that regard, we evaluated the ability of EUK134, a superoxide dismutase and catalase mimics, to protect human neuroblastoma cell line SK-N-MC against H(2)O(2) -induced oxidative stress. Our data clearly indicated that cell death induced by H(2)O(2) was reversed by EUK134. Likewise, lipid peroxidation, caspase-3 activation and intracellular reactive oxygen species formation all returned to control levels following pre-treatments with EUK134. Elevated phosphorylation of mitogen-activated protein kinases (MAPK) induced by H(2)O(2) in SK-N-MC cells was lowered by EUK134 in a dose-dependent manner. In addition, EUK134 decreased expression of pro-apoptotic genes p53 and Bax and enhanced expression of anti-apoptotic Bcl-2 gene. Taken together, these results suggest that EUK134 protects neuronal cells against H(2)O(2) toxicity by attenuating oxidative stress through inhibition of MAPK phosphorylation cascade.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antineoplastic Agents; Antioxidants; Apoptosis; Caspase 3; Catalase; Cell Death; Cell Line, Tumor; Dose-Response Relationship, Drug; Free Radical Scavengers; Genes, bcl-2; Humans; Hydrogen Peroxide; Lipid Peroxidation; Mitogen-Activated Protein Kinases; Neuroblastoma; Neuroprotective Agents; Organometallic Compounds; Reactive Oxygen Species; Salicylates; Superoxide Dismutase

Inflammation has been associated with the two classic lesions in the Alzheimer's (AD) brain, amyloid deposits and neurofibrillary tangles. Recent data suggest that Triflusal, a compound with potent anti-inflammatory effects in the central nervous system in vivo, might delay the conversion from amnestic mild cognitive impairment to a fully established clinical picture of dementia. In the present study, we investigated the effect of Triflusal on brain Abeta accumulation, neuroinflammation, axonal curvature and cognition in an AD transgenic mouse model (Tg2576). Triflusal treatment did not alter the total brain Abeta accumulation but significantly reduced dense-cored plaque load and associated glial cell proliferation, proinflammatory cytokine levels and abnormal axonal curvature, and rescued cognitive deficits in Tg2576 mice. Behavioral benefit was found to involve increased expression of c-fos and BDNF, two of the genes regulated by CREB, as part of the signal transduction cascade underlying the molecular basis of long-term potentiation. These results add preclinical evidence of a potentially beneficial effect of Triflusal in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Axons; Brain; Brain-Derived Neurotrophic Factor; Central Nervous System Agents; Cognition Disorders; Cytokines; Disease Models, Animal; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroglia; Plaque, Amyloid; Proto-Oncogene Proteins c-fos; Salicylates

This article from Coma et al. shows that a salicylic acid derivative Triflusal, a platelet aggregation inhibitor and irreversible inhibitor of COX-1, can correct defects in axonal curvature and cognition in an AD transgenic mouse model (Tg2576) (Coma et al., 2010). Here we discuss the controversy over the role of COX-1 in AD, which has not been considered carefully in part due to the presumed adverse gastrointestinal effects of COX-1 antagonism. However, recent clinical data from this group as well as other groups challenges this assumption that COX-1 antagonism will be associated with side effects. Most importantly this article raises critical questions about the role of COX-1, versus COX-2 versus both in Abeta pathogenesis. The animal model data in this article as well as the recently published trial data suggest that COX-1 may play an important role in early pathogenesis and should not be ignored as a potential target for early intervention.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Central Nervous System Agents; Cognition Disorders; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Humans; Membrane Proteins; Mice; Salicylates

Clinical data has shown that stroke exacerbates dementia in Alzheimer's disease (AD) patients. Previous work, combining rat models of AD and stroke have shown that neuroinflammation may be the common mediator between AD and stroke toxicity. This study examined the effects of triflusal (2-acetoxy-4-trifluoromethylbenzoic acid) in APP(23) transgenic mice receiving strokes. Six month-old APP(23) mice over-expressing mutant human amyloid precursor protein (APP) were used to model AD in this study. Unilateral injections of a potent vasoconstrictor, endothelin-1, into the striatum were used to mimic small lacunar infarcts. Immunohistochemical analysis was performed to examine AD-like pathology and inflammatory correlates of stroke and AD. APP(23) mice showed increases in AD-like pathology and inflammatory markers of AD in the cortex and hippocampus. Endothelin-induced ischemia triggered an inflammatory response along with increases in AD pathological markers in the region of the infarct. Triflusal reduced inflammation surrounding the endothelin-induced infarct only. At the dose used, anti-inflammatory treatment may be beneficial in reducing the AD and inflammatory correlates of stroke in a combined AD-stroke mouse model.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Antigens, CD; Brain Ischemia; Disease Models, Animal; Endothelin-1; Humans; Inflammation; Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B; Platelet Aggregation Inhibitors; Salicylates; Stroke; tau Proteins; Tumor Necrosis Factor-alpha

Recently, association of an interleukin-1A promoter polymorphism (-889, thymine/thymine (T/T)) with Alzheimer's disease was reported, suggesting that this cytokine may play an important role in disease development. To understand the mechanism underlying the interleukin-1A promoter's role in Alzheimer's disease, a study comparing promoter function of an interleukin-1A polymorphism was performed in the SVG astroglia cell line. The effects of thymine and cytosine on transcriptional activity of the interleukin-1A promoter were analyzed by testing luciferase-reporter activity in transfected SVG cells. Our results demonstrate that cytosine/thymine conversion increases activity of the interleukin-1A promoter in SVG cells. Both sodium salicylate and lovastatin are able to block induced promoter activities in astroglial cells. Induced promoter activity by the polymorphism (T/T) may result in the upregulation of interleukin-1alpha protein and "cytokine cycle" amplification, which may promote disease development.

Topics: Alzheimer Disease; Astrocytes; Cell Line; Cytosine; Humans; Interleukin-1alpha; Lovastatin; Luciferases; Plasmids; Polymorphism, Genetic; Promoter Regions, Genetic; Salicylates; Thymine; Transfection

Alzheimer disease is characterized by cerebral Abeta deposition, which we have recently discovered occurs also in the lens as cataracts in Alzheimer disease patients. Here we report the presence of significantly increased cataracts in the lenses of an Abeta-transgenic mouse model for Alzheimer disease and their amelioration upon treatment with EUK-189, a synthetic SOD/catalase mimetic. These data support an oxidative etiology for AD-associated lens cataracts and their potential to be treated preventatively with antioxidants.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Catalase; Cataract; Free Radicals; Humans; Mice; Mice, Transgenic; Models, Chemical; Organometallic Compounds; Oxygen; Salicylates; Superoxide Dismutase

Clinical data suggest that Alzheimer disease (AD) and stroke together potentiate cognitive impairment. Our rat model demonstrates that this interaction may be mediated through inflammatory cells and pathways. Thus, anti-inflammatory agents such as Triflusal, a nonsteroidal anti-inflammatory agent (NSAID), may provide neuroprotection for susceptible neurons in AD and cerebral ischemia.. AD was modeled by cerebroventricular injections of beta-amyloid (Abeta25-35) and subcortical lacunar infarcts by striatal endothelin injections. Inflammatory mechanisms were examined by immunohistochemical analysis. Behavioral tasks were assessed with the Montoya staircase test.. Triflusal reduced pathologic and inflammatory markers and functional deficits in rats receiving Abeta or endothelin alone but was less effective in the more severe pathology of the combined Abeta/endothelin model.. Higher doses or more prolonged treatment with NSAIDs may be required for more effective neuroprotection in combined AD and stroke conditions.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Astrocytes; Behavior, Animal; Brain; Brain Ischemia; Corpus Striatum; Cytokines; Disease Models, Animal; Endothelins; Glial Fibrillary Acidic Protein; Hippocampus; Immunohistochemistry; Inflammation; Microglia; Neurons; Peptides; Rats; Rats, Wistar; Salicylates; Temperature

Aspirin (acetylsalicylate) is an inexpensive drug that is used extensively to reduce cardiovascular disease risk. Emerging evidence suggests that aspirin reduces the risk of other chronic diseases such as certain forms of cancer. Salicylate may contribute to the disease reduction effects. It is present naturally in fruits and vegetables and individuals with a low intake of these foods may be 'salicylate deficient'. This deleterious state may constitute a significant public health threat. Interventions to prevent deficiency, such as low-dose aspirin programmes, could have substantial beneficial health impacts around the world.

Topics: Alzheimer Disease; Aspirin; Cardiovascular Diseases; Chronic Disease; Fruit; Humans; Neoplasms; Public Health; Salicylates; Vegetables

Previous studies have suggested that the use of nonsteroidal antiinflammatory drugs (NSAIDs) may help to prevent Alzheimer's disease. The results, however, are inconsistent.. We studied the association between the use of NSAIDs and Alzheimer's disease and vascular dementia in a prospective, population-based cohort study of 6989 subjects 55 years of age or older who were free of dementia at base line, in 1991. To detect new cases of dementia, follow-up screening was performed in 1993 and 1994 and again in 1997 through 1999. The risk of Alzheimer's disease was estimated in relation to the use of NSAIDs as documented in pharmacy records. We defined four mutually exclusive categories of use: nonuse, short-term use (1 month or less of cumulative use), intermediate-term use (more than 1 but less than 24 months of cumulative use), and long-term use (24 months or more of cumulative use). Adjustments were made by Cox regression analysis for age, sex, education, smoking status, and the use or nonuse of salicylates, histamine Hz-receptor antagonists, antihypertensive agents, and hypoglycemic agents.. During an average follow-up period of 6.8 years, dementia developed in 394 subjects, of whom 293 had Alzheimer's disease, 56 vascular dementia, and 45 other types of dementia. The relative risk of Alzheimer's disease was 0.95 (95 percent confidence interval, 0.70 to 1.29) in subjects with short-term use of NSAIDs, 0.83 (95 percent confidence interval, 0.62 to 1.11) in those with intermediate-term use, and 0.20 (95 percent confidence interval, 0.05 to 0.83) in those with long-term use. The risk did not vary according to age. The use of NSAIDs was not associated with a reduction in the risk of vascular dementia.. The long-term use of NSAIDs may protect against Alzheimer's disease but not against vascular dementia.

Topics: Aged; Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Cohort Studies; Dementia, Vascular; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Risk; Salicylates

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Creatine Kinase; Electron Spin Resonance Spectroscopy; Free Radicals; Gerbillinae; Glutamate-Ammonia Ligase; Humans; Hydroxylation; In Vitro Techniques; Lipid Peroxidation; Male; Neurons; Neurotoxins; Salicylates; Spin Labels; Synaptosomes

beta-Amyloid is a 39- to 43-amino-acid neurotoxic peptide that aggregates to form the core of Alzheimer disease-associated senile (amyloid) plaques. No satisfactory hypothesis has yet been proposed to explain the mechanism of beta-amyloid aggregation and toxicity. We present mass spectrometric and electron paramagnetic resonance spin trapping evidence that beta-amyloid, in aqueous solution, fragments and generates free radical peptides. beta-Amyloid fragments, at concentrations that previously have been shown to be neurotoxic to cultured neurons, can inactivate oxidation-sensitive glutamine synthetase and creatine kinase enzymes. Also, salicylate hydroxylation assays indicate that reactive oxygen species are generated by the beta-amyloid-(25-35) fragment during cell-free incubation. These results are formulated into a free radical-based unifying hypothesis for neurotoxicity of beta-amyloid and are discussed with reference to membrane molecular alterations in Alzheimer disease.

Topics: Alzheimer Disease; Amino Acid Sequence; Amyloid beta-Peptides; Chromatography, High Pressure Liquid; Electron Spin Resonance Spectroscopy; Free Radicals; Gas Chromatography-Mass Spectrometry; Molecular Sequence Data; Neurotoxins; Salicylates

Topics: Alzheimer Disease; Arthritis, Rheumatoid; Disease Susceptibility; Humans; Middle Aged; Risk Factors; Salicylates