Iron overload accelerates neuronal amyloid-β production and cognitive impairment in transgenic mice model of Alzheimer's disease

Iron dyshomeostasis is proving increasingly likely to be involved in the pathology of Alzheimer's disease (AD); yet, its mechanism is not well understood. Here, we investigated the AD-related mechanism(s) of iron-sulfate exposure in vitro and in vivo, using cultured primary cortical neurons and APP/PS1 AD-model mice, respectively. In both systems, we observed iron-induced disruptions of amyloid precursor protein (APP) processing, neuronal signaling, and cognitive behavior. Iron overload increased production of amyloidogenic KPI-APP and amyloid beta. Further, this APP misprocessing was blocked by MK-801 in vitro, suggesting the effect was N-methyl-d-aspartate receptor (NMDAR) dependent. Calcium imaging confirmed that 24 hours iron exposure led to disrupted synaptic signaling by augmenting GluN2B-containing NMDAR expression–GluN2B messenger RNA and protein levels were increased and promoting excessing extrasynaptic NMDAR signaling. The disrupted GluN2B expression was concurrent with diminished expression of the splicing factors, sc35 and hnRNPA1. In APP/PS1 mice, chronic iron treatment led to hastened progression of cognitive impairment with the novel object recognition discrimination index, revealing a deficit at the age of 4 months, concomitant with augmented GluN2B expression. Together, these data suggest iron-induced APP misprocessing and hastened cognitive decline occur through inordinate extrasynaptic NMDAR activation.     

Investigation of ethanol-induced impairment of spatial memory in γ2 heterozygous knockout mice

GABA_A receptors, the major inhibitory receptors in the mammalian central nervous system, are affected by a number of drug compounds, including ethanol. The pharmacological effects of certain drugs have been shown to be dependent upon specific GABA_A receptor subunits. Because benzodiazepines and ethanol have similar effect signatures, it has been hypothesized that these drugs share the γ2-containing GABA_A receptors as a mechanism of action. To probe the involvement of the γ2 subunit in ethanol's actions, spatial memory for the Morris water maze task was tested in γ2 heterozygous knockout mice and wild type littermate controls following ethanol administration at the following doses: 0.0, 1.25, 1.75, and 2.25 g/kg. While baseline learning and memory were unaffected by reduction of γ2 containing GABA_A receptors, ethanol dose-dependently impaired spatial memory equally in γ2 heterozygous knockouts and wild type littermate controls.     

HIF-1α change in serum and callus during fracture healing in ovariectomized mice

The purpose was to detect the effects of ovariectomy (OVX) on femoral fracture healing through different angiogenesis and HIF-1α expression in mice. Thirty-six young female C57 mice were randomized into two groups: OVX and age-matched intact control (CON). The femoral fracture was generated at 3 weeks after OVX or CON. At 2 or 4 weeks after fracture, the femoral fracture area was evaluated healing status by bone mineral density (BMD), callus formation and mineralization and neovascularization in callus, biomechanical analysis, and HIF-1α tests. OVX mice showed lower BMD as compared with CON mice. Callus geometric microstructural parameters of the femora in OVX mice were significantly lower than CON mice. OVX induced significant changes of biomechanical parameters in the femoral fracture healing area. The callus forming, callus neovascularization and HIF-1α tests in OVX mice were significantly lower than in CON mice. HIF-1α results have the positive proportion with osteoporotic fracture healing.     

Liraglutide protects against amyloid-β protein-induced impairment of spatial learning and memory in rats

Type 2 diabetes mellitus is a risk factor of Alzheimer's disease (AD), most likely linked to an impairment of insulin signaling in the brain. Liraglutide, a novel long-lasting glucagon-like peptide 1 (GLP-1) analog, facilitates insulin signaling and shows neuroprotective properties. In the present study, we analyzed the effects of liraglutide on the impairment of learning and memory formation induced by amyloid-β protein (Aβ), and the probable underlying electrophysiological and molecular mechanisms. We found that (1) bilateral intrahippocampal injection of Aβ_25–35 resulted in a significant decline of spatial learning and memory of rats in water maze tests, together with a serious depression of in vivo hippocampal late-phase long-term potentiation (L-LTP) in CA1 region of rats; (2) pretreatment with liraglutide effectively and dose-dependently protected against the Aβ_25–35-induced impairment of spatial memory and deficit of L-LTP; (3) liraglutide injection also activated cAMP signal pathway in the brain, with a nearly doubled increase in the cAMP contents compared with control. These results strongly suggest that upregulation of GLP-1 signaling in the brain, such as application of liraglutide, may be a novel and promising strategy to ameliorate the learning and memory impairment seen in AD.     

Kidney histologic alterations in α-Galactosidase-deficient mice

Fabry disease is a rare X-linked disorder caused by mutations in the α-galactosidase gene (GLA), the resultant deficiency of lysosomal α-galactosidase enzyme activity leading to systemic accumulation of globotriaosylceramide and other glycosphingolipids. GLA knockout mice (“Fabry mice”) were generated as an animal model for Fabry disease but, as they do not manifest progressive chronic kidney disease (CKD), their relevance as a model for human Fabry nephropathy is uncertain. We evaluated the histological alterations in the kidneys of Fabry mice at different ages, as contrasted to those observed in wild-type mice. Furthermore, we compared the renal histological alterations of Fabry mice to the kidney pathology reported in patients with Fabry disease at comparable age ranges and across different CKD stages, using a scoring system that has been developed for Fabry nephropathy. Fabry mice are phenotypically different from wild-type mice, displaying progressive age-related accumulation of glycosphingolipids in all types of renal cells. There were no statistically significant differences between Fabry mice and Fabry patients in the prevalence of glycosphingolipid storage per renal cell type with the exceptions of mesangial (higher in humans) and proximal tubular cells (higher in mice). However, Fabry mice lack the nonspecific histological glomerulosclerotic and interstitial fibrotic renal lesions that best correlate with progressive CKD in Fabry patients, and do not develop large podocyte inclusions. We postulate that the elucidation of the mechanisms underlying these species differences, may contribute important clues to a better understanding of the pathogenesis of Fabry nephropathy.     

Metabolic abnormalities and hypoleptinemia in α-synuclein A53T mutant mice

Parkinson's disease (PD) patients frequently display loss of body fat mass and increased energy expenditure, and several studies have outlined a relationship between these metabolic abnormalities and disease severity, yet energy metabolism is largely unstudied in mouse models of PD. Here we characterize metabolic and physiologic responses to a high calorie diet (HCD) in mice expressing in neurons a mutant form of human α-synuclein (A53T) that causes dominantly inherited familial forms of the disease. A53T (SNCA) and wild type (WT) littermate mice were placed on a HCD for 12 weeks and evaluated for weight gain, food intake, body fat, blood plasma leptin, hunger, glucose tolerance, and energy expenditure. Results were compared with both SNCA and WT mice on a control diet. Despite consuming similar amounts of food, WT mice gained up to 66% of their original body weight on a HCD, whereas SNCA mice gained only 17%. Further, after 12 weeks on a HCD, magnetic resonance imaging analysis revealed that WT mice had significantly greater total and visceral body fat compared with SNCA mice (p < 0.007). At the age of 24 weeks SNCA mice displayed significantly increased hunger compared with WT (p < 0.03). At the age of 36 weeks, SNCA mice displayed significant hypoleptinemia compared with WT, both on a normal diet and a HCD (p < 0.03). The HCD induced insulin insensitivity in WT, but not SNCA mice, as indicated by an oral glucose tolerance test. Finally, SNCA mice displayed greater energy expenditure compared with WT, as measured in a Comprehensive Laboratory Animal Monitoring System, after 12 weeks on a HCD. Thus, SNCA mice are resistant to HCD-induced obesity and insulin resistance and display reduced body fat, increased hunger, hypoleptinemia and increased energy expenditure. Our findings reveal a profile of metabolic dysfunction in a mouse model of PD that is similar to that of human PD patients, thus providing evidence that α-synuclein pathology is sufficient to drive such metabolic abnormalities and providing an animal model for discovery of the underlying mechanisms and potential therapeutic interventions.     

B-lymphocyte depletion ameliorates Sjögren's syndrome in Id3 knockout mice

Sjögren''s syndrome is an autoimmune disease in which immune cells chronically attack the lachrymal and salivary glands. The Id3 knockout mouse is a newly established animal model for primary Sjögren''s syndrome. To address the role of B cells in Sjögren''s syndrome and autoimmune disease, we studied the effect of CD20 monoclonal antibody treatment on the disease in Id3 knockout mice. Antibody treatment at 2-month intervals led to efficient and sustained B-cell depletion in Id3 knockout mice. A significant improvement of histopathology was observed accompanied by the recovery of saliva secretory function after CD20 antibody treatment. We further show that serum immunoglobulin G3, which is abnormally high in untreated Id3 knockout mice, was reduced after CD20 antibody treatment. This study establishes a new animal model for immunotherapy of Sjögren''s symptoms and suggests a possible link between immunoglobulin G3 and disease pathology in Id3 knockout mice.     

Environmental enrichment ameliorated high-fat diet-induced Aβ deposition and memory deficit in APP transgenic mice

The pathogenesis of Alzheimer's disease (AD) is tightly associated with metabolic dysfunctions. In particular, a potential link between type 2 diabetes (T2DM) and AD has been suggested epidemiologically, clinically, and experimentally, and some studies have suggested that exercise or dietary intervention reduces risk of cognitive decline. However, there is little solid molecular evidence for the effective intervention of metabolic dysfunctions for prevention of AD. In the present study, we established the AD model mice with diabetic conditions through high-fat diet (HFD) to examine the effect of environmental enrichment (EE) on HFD-induced AD pathophysiology. Here, we demonstrated that HFD markedly deteriorated memory impairment and increased β-amyloid (Aβ) oligomers as well as Aβ deposition in amyloid precursor protein (APP) transgenic mice, which was reversed by exposure to an enriched environment for 10 weeks, despite the continuation of HFD. These studies provide solid evidence that EE is a useful intervention to ameliorate behavioral changes and AD pathology in HFD-induced aggravation of AD symptoms in APP transgenic mice.     

Berberine ameliorates β-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer's disease transgenic mouse model

The accumulation of β-amyloid (Aβ) peptide derived from abnormal processing of amyloid precursor protein (APP) is a common pathological hallmark of Alzheimer's disease (AD) brains. In this study, we evaluated the therapeutic effect of berberine (BBR) extracted from Coptis chinensis Franch, a Chinese medicinal herb, on the neuropathology and cognitive impairment in TgCRND8 mice, a well established transgenic mouse model of AD. Two-month-old TgCRND8 mice received a low (25 mg/kg per day) or a high dose of BBR (100 mg/kg per day) by oral gavage until 6 months old. BBR treatment significantly ameliorated learning deficits, long-term spatial memory retention, as well as plaque load compared with vehicle control treatment. In addition, enzyme-linked immunosorbent assay (ELISA) measurement showed that there was a profound reduction in levels of detergent-soluble and -insoluble β-amyloid in brain homogenates of BBR-treated mice. Glycogen synthase kinase (GSK)3, a major kinase involved in APP and tau phosphorylation, was significantly inhibited by BBR treatment. We also found that BBR significantly decreased the levels of C-terminal fragments of APP and the hyperphosphorylation of APP and tau via the Akt/glycogen synthase kinase 3 signaling pathway in N2a mouse neuroblastoma cells stably expressing human Swedish mutant APP695 (N2a-SwedAPP). Our results suggest that BBR provides neuroprotective effects in TgCRND8 mice through regulating APP processing and that further investigation of the BBR for therapeutic use in treating AD is warranted.     

Inter-identity amnesia in dissociative identity disorder: a simulated memory impairment?

BACKGROUND: Although included in the current edition of the DSM, there does not seem to be consensus among mental health professionals regarding the diagnostic status and scientific validity of dissociative identity disorder (DID). This study was aimed at the detection of simulation of inter-identity amnesia in DID. METHOD: A sample of 22 DID patients was included, together with a matched control sample of subjects instructed to simulate inter-identity amnesia, a guessor group that had no knowledge of the stimulus material and a normal control group. A multiple-choice recognition test was included. The rate of incorrect answers was determined. Moreover, the specific simulation strategy used was examined by providing subjects with a range of choices that varied in extent of disagreement with the correct answer and determining whether plausible or implausible answer alternatives were selected. RESULTS: On the recognition test DID patients selected incorrect answers above chance like simulators. Patients thus seem to use their knowledge of the correct answer in determining their given answer. They were not characterized by a well-thought-out simulating behaviour style, as indicated by the differences in selection of specific answer alternatives found between patients and simulators. CONCLUSIONS: DID patients were found not to be characterized by an actual memory retrieval inability, in contrast to their subjective reports. Instead, it is suggested that DID may more accurately be considered a disorder characterized by meta-memory problems, holding incorrect beliefs about their own memory functioning.     

Astragaloside inhibits IL-1β-induced inflammatory response in human osteoarthritis chondrocytes and ameliorates the progression of osteoarthritis in mice

Abstract

Background: Osteoarthritis (OA) is a chronic joint-degeneration disease and accounts for the most frequent arthritis in aging people. OA is characterized by the degeneration of articular cartilage, subchondral bone sclerosis and synovitis. Inflammation as an important role in OA progression, in that anti-inflammatory agents could effectively inhibit the development of OA with minimal side effects, therefore developing a nature anti-inflammatory compound will be a promising therapy for treating OA.

Methods: We treated patient-derived chondrocytes and mouse models of OA with astragaloside, an effective component of astragalus membranaceus, and measured its effect on pro-inflammatory cytokines and OA progression in mice.

Results: In vitro, astragaloside induced a dose-dependent inhibition of IL-1β-induced the production of inflammatory factors, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), nitric oxide (NO), prostaglandin E2 (PGE2), expression of MMP 13 and ADAMTS-5, and the activation of NF-κB signaling. In vivo, astragaloside ameliorate the degeneration of cartilage in mouse model of OA.

Conclusion: Astragaloside potentially serve as a promising and effective therapeutic agent for treating OA patients.     

TNF-α receptor 1 deficiency reduces antigen-presenting capacity of Schwann cells and ameliorates experimental autoimmune neuritis in mice

Tumor necrosis factor-α (TNF-α) is a pleiotropic pro-inflammatory cytokine with potentially neurodestructive effects and plays a pivotal role in autoimmune demyelinating disease. To address the role of TNF-α in the pathogenesis of experimental autoimmune neuritis (EAN), the current study investigated the antigen-presenting capacity of Schwann cells (SCs) in EAN induced by P0 protein peptide 106–125 in TNF-α recepter 1 deficient (TNFR1^−/−) mice. The antigen-presenting capacity of SCs was assessed by the expression of MHC class II (MHCII), CD40, CD80 and CD86 molecules on activated SCs as well as by induction of T cell proliferation in co-cultures of P0 protein peptide 106–125 specific T cells with activated SCs. In addition, the expression of inducible nitric oxide synthase (iNOS) was measured in activated SCs by flow cytometry. TNFR1^−/− EAN mice developed significantly delayed and reduced clinical signs of EAN compared to wild type EAN mice. In parallel, the expression of MHCII, CD80 and iNOS on SCs were decreased in TNFR1^−/− mice compared to wild type mice. Likewise, proliferation of P0 protein peptide 106–125 specific T cells simulated by activated SCs of TNFR1^−/− EAN mice was lower than that of wild type EAN mice. Our data suggest that TNF-α may exert pro-inflammatory effects in EAN via TNFR1 by up-regulating the antigen-presenting function and iNOS production of SCs.     

Alterations in corticostriatal synaptic plasticity in mice overexpressing human α-synuclein

Most forms of Parkinson's disease (PD) are sporadic in nature, but some have genetic causes as first described for the α-synuclein gene. The α-synuclein protein also accumulates as insoluble aggregates in Lewy bodies in sporadic PD as well as in most inherited forms of PD. The focus of the present study is the modulation of synaptic plasticity in the corticostriatal pathway of transgenic (Tg) mice that overexpress the human α-synuclein protein throughout the brain (ASOTg). Paired-pulse facilitation was detected in vitro by activation of corticostriatal afferents in ASOTg mice, consistent with a presynaptic effect of elevated human α-synuclein. However basal synaptic transmission was unchanged in ASOTg, suggesting that human α-synuclein could impact paired-pulse facilitation via a presynaptic mechanism not directly related to the probability of neurotransmitter release. Mice lacking α-synuclein or those expressing normal and A53T human α-synuclein in tyrosine hydroxylase-containing neurons showed, instead, paired-pulse depression. High-frequency stimulation induced a presynaptic form of long-term depression solely in ASOTg striatum. A presynaptic, N-methyl-d-aspartate receptor-independent form of chemical long-term potentiation induced by forskolin (FSK) was enhanced in ASOTg striatum, while FSK-induced cAMP levels were reduced in ASOTg synaptoneurosome fractions. Overall the results suggest that elevated human α-synuclein alters presynaptic plasticity in the corticostriatal pathway, possibly reflecting a reduction in glutamate at corticostriatal synapses by modulation of adenylyl cyclase signaling pathways. ASOTg mice may recapitulate an early stage in PD during which overexpressed α-synuclein dampens corticostriatal synaptic transmission and reduces movement.     

Preventive and therapeutic oral administration of the pentacyclic triterpene α,β-amyrin ameliorates dextran sulfate sodium-induced colitis in mice: The relevance of cannabinoid system

The pentacyclic triterpene α,β-amyrin has been previously reported as an effective compound in the treatment of several inflammatory conditions. Recent evidence indicates that α,β-amyrin displayed its effects through interaction with the cannabinoid pathway. We assessed the anti-inflammatory effects of the α,β-amyrin in the dextran sulfate sodium (DSS)-induced colitis in mice and investigated whether its effects were associated with the interaction with the cannabinoid system. Our results showed that the oral preventive or therapeutic treatment with α,β-amyrin significantly reduced disease activity, body weight loss, colonic damage, as well as colonic myeloperoxidase and N-acetylglucosaminidase activities. Moreover, α,β-amyrin decreases the colonic pro-inflammatory mediators tumor necrosis factor (TNF)-α, interleukin (IL)-1β and keratinocyte-derived chemokine (CXCL1/KC), while up-regulating the IL-4 levels. Additionally, we also observed that the α,β-amyrin caused a significant reduction of the adhesion molecules mRNA expression for intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), platelet cell adhesion molecule 1 (PCAM-1), β₂-integrin and protein expression for proliferation marker Ki67, the macrophage molecule CD68 and for adhesion molecule P-selectin. Interestingly, our results also showed that the cannabinoid receptor 1 (CB₁), but not CB₂, pharmacological blockade significantly reversed the beneficial effects of α,β-amyrin in DSS-induced colitis. Besides, our data demonstrated that mRNA expression for both the endocannabinoid hydrolase monoglyceride lipase 1 (MGL1) and fatty acid amide hydrolase (FAAH) were significantly reduced in the colon of α,β-amyrin-treated mice. Altogether, these results suggest that the α,β-amyrin might possess potential therapeutic interest for the treatment of IBD, and also provide new insights for the underlying mechanisms.     

Subjective memory complaints in the elderly: a sign of cognitive impairment?

OBJECTIVES:

Cognitive impairment in the elderly is frequently overlooked by general practitioners. The use of subjective memory complaints as a sign of cognitive impairment by the general practice is controversial.

METHODS:

Elderly individuals (N = 248) were asked whether they had memory complaints and underwent a cognitive impairment screening. Subjects classified as exhibiting “probable cognitive impairment” underwent a complete cognitive evaluation, and the final diagnoses were established by expert consensus.

RESULTS:

A total of 147 patients presented with subjective memory complaints, and 43 were further classified as demented or “cognitively impaired not demented”. Subjective memory complaints presented a sensitivity of 100% and a negative predictive value of 100%.

CONCLUSION:

Subjective memory complaints are an indicator for cognitive impairment screening.     

Fragrant environment with α-pinene decreases tumor growth in mice

Stress is believed to be harmful to not only mental but also physical health. However, proving a link between stress and disease is difficult. A recent study reported that an environmental enrichment reduced cancer growth via the hypothalamic-pituitary-adrenal axis and leptin. Here, we report that mice kept in a fragrant environment enriched with α-pinene show reduced melanoma growth. Tumor volume of mice under the α-pinene environment was about 40% smaller than that in the control mice. α-Pinene had no inhibitory effect on melanoma cell proliferation in vitro, suggesting that this effect was not a direct effect of α-pinene. These results suggest that the provision of a fragrant environment may be an important factor in the therapeutic approach to cancer.     

Colocalization of GPR120 with phospholipase-Cβ2 and α-gustducin in the taste bud cells in mice

A recent study has demonstrated that the G-protein coupled receptor GPR120 is expressed in the taste bud cells in rats. In this study, we have identified the types of taste cell that express GPR120 in C57/BL6 mice. Double immunostaining for GPR120 and the markers of type II taste cells (phospholipase-Cβ2 and α-gustducin) revealed that the majority of the GPR120-positive taste cells are type II taste cells. In contrast, it was observed that GPR120 was rarely colocalized with the marker of type III cells (neuronal cell adhesion molecule). These results suggested that GPR120 is mainly expressed in the type II taste cells and might function as a sensor for dietary fat.     

Chronic nicotine restores normal Aβ levels and prevents short-term memory and E-LTP impairment in Aβ rat model of Alzheimer's disease

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by increased deposition of beta-amyloid (Aβ) peptides and progressive cholinergic dysfunction in regions of the brain involved in learning and memory processing. In AD, progressive accumulation of Aβ peptide impairs nicotinic acetylcholine receptor (nAChR) function by an unknown mechanism believed to involve α₇- and α₄β₂-nAChR blockade. The three approaches of the current study evaluated the effects of chronic nicotine treatment in the prevention of Aβ-induced impairment of learning and short-term memory. Rat AD model was induced by 14-day i.c.v. osmotic pump infusion of a 1:1 mixture of 300 pmol/day Aβ_1-40/Aβ_1-42 or Aβ_40-1 (inactive peptide, control). The effect of nicotine (2 mg/(kg day)) on Aβ-induced spatial learning and memory impairments was assessed by evaluation of performance in the radial arm water maze (RAWM), in vivo electrophysiological recordings of early-phase long-term potentiation (E-LTP) in urethane-anesthetized rats, and immunoblot analysis to determine changes in the levels of beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), Aβ and memory-related proteins. The results indicate that 6 weeks of nicotine treatment reduced the levels of Aβ_1-40 and BACE1 peptides in hippocampal area CA1 and prevented Aβ-induced impairment of learning and short-term memory. Chronic nicotine also prevented the Aβ-induced inhibition of basal synaptic transmission and LTP in hippocampal area CA1. Furthermore, chronic nicotine treatment prevented the Aβ-induced reduction of α₇- and α₄-nAChR. These effects of nicotine may be due, at least in part, to upregulation of brain derived neurotropic factor (BDNF).     

Blockade of IL-33 ameliorates Con A-induced hepatic injury by reducing NKT cell activation and IFN-γ production in mice

IL-33, a recently described member of the IL-1 family, has been identified as a cytokine endowed with pro-Th2 type functions. To date, there are only limited data on its role in physiological and pathological hepatic immune responses. In this study, we examined the role of IL-33 in immune-mediated liver injury by exploring the model of concanavalin A (Con A)-induced hepatitis. We observed that the level of IL-33 expression in the liver was dramatically increased at 12?h after Con A injection. Meanwhile, ST2L, the receptor of IL-33, was significantly up-regulated in lymphocytes including T and natural killer T (NKT) cells, especially in NKT cells. Moreover, administration of recombinant IL-33 exacerbated Con A-induced hepatitis, while pretreatment of IL-33-blocking antibody or psST2-Fc plasmids showed a protective effect probably by inhibiting the activation of late stage of T cells and NKT cells and also decreasing the production of the cytokine IFN-??. Furthermore, depletion of NKT cells abolished the protective effect of IL-33-blocking antibody, and IL-33 failed to exacerbate Con A-induced hepatitis in IFN-??^?/? mice. These data suggested the critical roles of NKT cells and IFN-?? in the involvement of IL-33 in Con A-induced hepatitis. Blockade of IL-33 may represent a novel therapeutic strategy through IL-33/ST2L signal to prevent immune-mediated liver injury.     

Modulation of lipopolysaccharide-induced memory insult, γ-secretase,and neuroinflammation in triple transgenic mice by 5-lipoxygenase

Besides amyloid and tau pathology, a constant feature of Alzheimer's disease (AD) is an intense inflammatory response, which is considered an active player in its pathogenesis. The 5-Lipoxygenase (5LO) is a proinflammatory enzyme and an endogenous modulator of AD-like phenotype in mouse models of the disease. To further understand the role of 5LO in AD pathogenesis, we exposed the triple transgenic (3×Tg) and 3×Tg/5LO knockout mice to lipopolysaccharide (LPS), a known inducer of neuroinflammation, and evaluated its effect on their AD-like phenotype. 3×Tg mice treated with LPS manifested a worsening of behavior, γ-secretase up-regulation, and increased neuroinflammatory responses. These effects were completely prevented in 3×Tg mice genetically deficient for 5LO. By contrast, the absence of 5LO did not protect against increase in tau phosphorylation at specific epitopes that were mediated by the activation of the cyclin-dependent kinase 5. Our data demonstrate that the 5LO pathway affects key neuropathological features of the AD-like phenotype (behavior, abeta, microgliosis, astrocytosis) but not others (tau pathology) in the LPS-dependent neuroinflammation model. The opposite ways whereby 5LO influences the LPS-dependent effects in vivo supports the complex nature of the neuroinflammatory response in AD and its differential role in modulating amyloid and tau neuropathology.