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Several clinical studies reported that the elevated expression of Chitinase-3-like 1 (CHI3L1) was observed in patients suffering from a wide range of diseases: cancer, metabolic, and neurological diseases. However, the role of CHI3L1 in AD is still unclear. Our previous study demonstrated that 2-({3-[2-(1-Cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}culfanyl)-N-(4-ethylphenyl)butanamide, a CHI3L1 inhibiting compound, alleviates memory and cognitive impairment and inhibits neuroinflammation in AD mouse models. In this study, we studied the detailed correlation of CHI3L1 and AD using serum from AD patients and using CHI3L1 knockout (KO) mice with Aβ infusion (300 pmol/day, 14 days). Serum levels of CHI3L1 were significantly elevated in patients with AD compared to normal subjects, and receiver operating characteristic (ROC) analysis data based on serum analysis suggested that CHI3L1 could be a significant diagnostic reference for AD. To reveal the role of CHI3L1 in AD, we investigated the CHI3L1 deficiency effect on memory impairment in Aβ-infused mice and microglial BV-2 cells. In CHI3L1 KO mice, Aβ infusion resulted in lower levels of memory dysfunction and neuroinflammation compared to that of WT mice. CHI3L1 deficiency selectively inhibited phosphorylation of ERK and IκB as well as inhibition of neuroinflammation-related factors in vivo and in vitro. On the other hand, treatment with recombinant CHI3L1 increased neuroinflammation-related factors and promoted phosphorylation of IκB except for ERK in vitro. Web-based gene network analysis and our results showed that CHI3L1 is closely correlated with PTX3. Moreover, in AD patients, we found that serum levels of PTX3 were correlated with serum levels of CHI3L1 by Spearman correlation analysis. These results suggest that CHI3L1 deficiency could inhibit AD development by blocking the ERK-dependent PTX3 pathway. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) is the most common form of dementia. Depression is one of the most critical psychiatric complications of AD, and 20%–30% of patients with AD experience symptoms of depression. Phospho‐glycogen synthase kinase‐3 beta (GSK3β) is known to be associated with AD and depression. Furthermore, the role of disheveled (DVL) is known to regulate GSK3β. Moreover, presenilin‐2 (PS2) and DVL have cross‐talk with each other. Also, it is widely hypothesized that stress leads to hypersecretion of cortisol and is thus associated with depression. Dickkopf WNT signaling pathway inhibitor‐1 (DKK‐1) is a crucial factor regulating depression and both amyloid beta (Aβ) and phosphorylation of tau are widely known as a biomarker of AD. Methods: To investigate the relationship between AD and depression, and possible pathways connecting the two diseases, we examined memory function and depression‐related behavior test results in PS2 knock‐in AD mice (PS2 MT). Next, we confirmed that there are relationships between DVL, depression, and cognitive disease through the comparative toxicogenomics database (https://ctdbase.org) and STRING (https://string‐db.org) database. Results: PS2 knock‐in mice showed much more severe memory impairment and depression than PS2 wild‐type mice (PS2 WT). In AD‐related behavioral experiments, PS2 MT mice showed more memory dysfunction compared with PS2 WT group mice. Moreover, Aβ and phosphorylation of tau showed higher expression in PS2 MT mice than in PS2 WT mice. Depression‐related behavioral tests showed that PS2 MT mice exhibited more depressive behaviors than PS2 WT mice. Furthermore, both higher cortisol levels and higher expression of DKK‐1 were found in PS2 MT mice relative to PS2 WT mice. The results indicated that there is a relationship between DVL and the release of AD‐related mediators and expression of the depression‐related glucocorticoid receptor and DKK‐1. In the PS2 knock‐in group, DVL was significantly decreased compared with the PS2 WT group. Conclusion: Depression increases the risk of developing AD and other forms of dementia. Recent evidence indicates that depression symptoms could trigger changes in memory and thinking over time. However, it is recognized that there are no drugs to facilitate a full recovery for both AD and depression. However, our results suggest that AD and depression could be associated, and DVL could be a significant target for the association between AD and depression. [ABSTRACT FROM AUTHOR]

Abstract Background 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. Methods 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). Results 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. Conclusion 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.

Alzheimer's disease (AD) is the most common form of dementia and is characterized by deposition of amyloid beta (Aβ) in the brain. The components of the herb Magnolia officinalis are known to have antiinflammatory, antioxidative and neuroprotective activities. In this study we investigated the effects of ethanol extract of M. officinalis on memory dysfunction and amyloidogenesis in a transgenic mouse model of AD. Oral pretreatment of ethanol extract of M. officinalis (10 mg/kg in 0.05% ethanol) into drinking water for 3 months inhibited memory impairment and Aβ deposition in the brain of Tg2576 mice. Ethanol extract of M. officinalis also decreased activity of β-secretase, cleaving Aβ from amyloid precursor protein (APP), and expression of β-site APP cleaving enzyme 1 (BACE1), APP and its product, C99. Our results showed that ethanol extract of M. officinalis effectively prevented memory impairment via down-regulating β-secretase activity. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), the most common form of dementia, is characterized by memory deficits and deposition of amyloid-β (Aβ) in the brain. It has been known that neuroinflammation and oxidative stress are critical factors in the development of AD. 4-O-methylhonokiol, an extract from Magnolia officinalis, is known to have anti-inflammatory and anti-oxidative effects. Thus, we investigated the properties of 4-O-methylhonokiol against progression and development of AD in Tg2576 mice. Tg2576 mice models show memory impairment and AD-like pathological features including Aβ deposition. Oral administration of 4-O-methylhonokiol through drinking water (1 mg/kg in 0.0002% Tween 80) for 12 weeks not only prevented memory impairment but also inhibited Aβ deposition. In addition, 4-O-methylhonokiol decreased β-secretase activity, oxidative lipid and protein damage levels, activation of astrocytes and microglia cells, and generation of IL-1β and TNF-α with increase of glutathione level in the brain. Our results showed that 4-O-methylhonokiol effectively prevented memory impairment by down-regulating β-secretase activity through inhibition of oxidative stress and neuroinflammatory responses in Tg2576 transgenic mice. [ABSTRACT FROM AUTHOR]

Neuroinflammation is implicated for amyloidogenesis. Sulfur compounds extracted from garlic have been shown to have anti-inflammatory properties. Previously, we have investigated that thiacremonone, a sulfur compound isolated from garlic has anti-inflammatory effects. To investigate thiacremonone's potential effect on anti-neuroinflammation and anti-amyloidogenesis, 4 week old ICR mice were given different doses of thiacremonone (1, 3, and 10 mg/kg) in drinking water for 1 month and received intraperitoneal injection of lipopolysaccharide (LPS) (250 μg/kg/day) at last 7 days of treatment. Our data show thiacremonone decreased LPS-induced memory impairment, glial activation, pro-inflammatory mediators' expression, and amyloidogenesis. In an in vitro study, we obtained similar results, with thiacremonone (1, 2, and 5 μg/ml) effectively decreased LPS (1 μg/ml)-induced glial activation and inflammatory mediators generation which are implicated in amyloidogenesis. Our data also demonstrated that thiacremonone inhibited LPS-induced amyloidogenesis in cultured astrocytes and microglial BV-2 cells. NF-κB, a critical transcriptional factor regulating not only inflammation but also amyloid-β generation, was inhibited by thiacremonone via blocking of phosphorylation of IκBα in mice brain as well as cultured astrocytes and microglial BV-2 cells. These results indicated that the anti-inflammatory compound, thiacremonone, inhibited neuroinflammation and amyloidogenesis through inhibition of NF-κB activity, and thus could be applied for intervention of inflammation-related neurodegenerative disease including Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Accumulations of amyloid-β (Aβ) and oxidative damage are critical pathological mechanisms in the development of Alzheimer's disease (AD). We previously found that 4-O-methylhonokiol, a compound extracted from Magnolia officinalis, improved memory dysfunction in Aβ-injected and presenilin 2 mutant mice through the reduction of accumulated Aβ. To investigate mechanisms of the reduced Aβ accumulation, we examined generation, degradation, efflux and aggregation of Aβ in Swedish AβPP AD model (AβPPsw) mice pre-treated with 4-O-methylhonokiol (1.0 mg/kg) for 3 months. 4-O-methylhonokiol treatment recovered memory impairment and prevented neuronal cell death. This memory improving activity was associated with 4-O-methylhonokiol-induced reduction of Aβ1-42 accumulation in the brains of AβPPsw mice. According to the reduction of Aβ1-42 accumulation, 4-O-methylhonkiol modulated oxidative damage sensitive enzymes. 4-O-methylhonkiol decreased expression and activity of brain beta-site AβPP cleaving enzyme (BACE1), but increased clearance of Aβ in the brain through an increase of expressions and activities of Aβ degradation enzymes; insulin degrading enzyme and neprilysin. 4-O-methylhonkiol also increased expression of Aβ transport molecule, low density lipoprotein receptor-related protein-1 in the brain and liver. 4-O-methylhonkiol decreased carbonyl protein and lipid peroxidation, but increased glutathione levels in the brains of AβPPsw mice suggesting that oxidative damage of protein and lipid is critical in the impairment of those enzyme activities. 4-O-methylhonokiol treatment also prevented neuronal cell death in the AβPPsw mousee brain through inactivation of caspase-3 and BAX. These results suggest that 4-O-methylhonokiol might prevent the development and progression of AD by reducing Aβ accumulation through an increase of clearance and decrease of Aβ generation via antioxidant mechanisms. [ABSTRACT FROM AUTHOR]

Astaxanthin (AXT), a xanthophyll carotenoid compound, has potent antioxidant, anti-inflammatory and neuroprotective properties. Neuroinflammation and oxidative stress are significant in the pathogenesis and development of Alzheimer's disease (AD). Here, we studied whether AXT could alleviate neuroinflammation, oxidative stress and memory loss in lipopolysaccharide (LPS) administered mice model. Additionally, we investigated the anti-oxidant activity and the anti-neuroinflammatory response of AXT in LPS-treated BV-2 microglial cells. The AXT administration ameliorated LPS-induced memory loss. This effect was associated with the reduction of LPS-induced expression of inflammatory proteins, as well as the production of reactive oxygen species (ROS), nitric oxide (NO), cytokines and chemokines both in vivo and in vitro. AXT also reduced LPS-induced β-secretase and Aβ1–42 generation through the down-regulation of amyloidogenic proteins both in vivo and in vitro. Furthermore, AXT suppressed the DNA binding activities of the signal transducer and activator of transcription 3 (STAT3). We found that AXT directly bound to the DNA- binding domain (DBD) and linker domain (LD) domains of STAT3 using docking studies. The oxidative stress and inflammatory responses were not downregulated in BV-2 cells transfected with DBD-null STAT3 and LD-null STAT3. These results indicated AXT inhibits LPS-induced oxidant activity, neuroinflammatory response and amyloidogenesis via the blocking of STAT3 activity through direct binding. [ABSTRACT FROM AUTHOR]

Chitinase 3-like 1 (CHI3L1) is a secreted glycoprotein that mediates inflammation, macrophage polarization, apoptosis, and carcinogenesis. The expression of CHI3L1 is strongly increased by various inflammatory and immunological conditions, including rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, and several cancers. However, its physiological and pathophysiological roles in the development of cancer and neurodegenerative and inflammatory diseases remain unclear. Several studies have reported that CHI3L1 promotes cancer proliferation, inflammatory cytokine production, and microglial activation, and that multiple receptors, such as advanced glycation end product, syndecan-1/αVβ3, and IL-13Rα2, are involved. In addition, the pro-inflammatory action of CHI3L1 may be mediated via the protein kinase B and phosphoinositide-3 signaling pathways and responses to various pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, interleukin-6, and interferon-γ. Therefore, CHI3L1 could contribute to a vast array of inflammatory diseases. In this article, we review recent findings regarding the roles of CHI3L1 and suggest therapeutic approaches targeting CHI3L1 in the development of cancers, neurodegenerative diseases, and inflammatory diseases. [ABSTRACT FROM AUTHOR]

Neuroinflammation is significant in the pathogenesis and development of Alzheimer's disease (AD). Previously, we showed lipopolysaccharide (LPS)-induced neuroinflammation caused memory impairment. We investigated the possible preventive effects of punicalagin (PUN), a component of pomegranate, on memory deficiency caused by LPS, along with the fundamental mechanisms. LPS-treated cultured astrocytes and microglial BV-2 cells were investigated for anti -neuroinflammatory effects of PUN. PUN (1.5 mg/kg) ameliorates LPS (250 μg/kg daily 7 times)-induced memory impairment as well as prevents the LPS-induced expression of inflammatory proteins. In in vitro study, we also found that PUN (1 μg/ml) inhibited the LPS-(10, 20 and 50 μM) induced expression of iNOS and Cox-2 as well as the production of ROS, NO, TNF-α and IL-1β. PUN also suppress activation of NF-κB via inhibition of IκB degradation as well as p50 and p65 translocation into the nucleus in LPS treated mouse brain and cultured astrocytes and microglial BV-2 cells. Consistent with the inhibitory effect on neuro inflammation, PUN inhibited LPS-induced Aβ 1-42 generation through down-regulation of APP and BACE1 expression in in vivo and in vitro study. Moreover, PUN directly binds to NF-κB subunit p50 evidenced by a docking model and pull down assay. These results suggest that PUN inhibits LPS-induced memory impairment via anti-inflammatory and anti -amylogenic mechanisms through inhibition of NF-κB activation. [ABSTRACT FROM AUTHOR]

Abstract: Neuroinflammation has been known to play a critical role in the pathogenesis of Alzheimer''s disease (AD) through amyloidogenesis. In a previous study, we found that systemic inflammation by intraperitoneal (ip) injection of lipopolysaccharide (LPS) induces neuroinflammation and triggers memory impairment. In this present study, we investigated the inhibitory effects of epigallocatechin-3-gallate (EGCG) on the systemic inflammation-induced neuroinflammation and amyloidogenesis as well as memory impairment. ICR mice were orally administered with EGCG (1.5 and 3 mg/kg) for 3 weeks, and then the mice were treated by ip injection of LPS (250 μg/kg) for 7 days. We found that treatment of LPS induced memory-deficiency-like behavior and that EGCG treatment prevented LPS-induced memory impairment and apoptotic neuronal cell death. EGCG also suppressed LPS-induced increase of the amyloid beta-peptide level and the expression of the amyloid precursor protein (APP), β-site APP cleaving enzyme 1 and its product C99. In addition, we found that EGCG prevented LPS-induced activation of astrocytes and elevation of cytokines including tumor necrosis factor-α, interleukin (IL)-1β, macrophage colony-stimulating factor, soluble intercellular adhesion molecule-1 and IL-16, and the increase of inflammatory proteins, such as inducible nitric oxide synthase and cyclooxygenase-2, which are known factors responsible for not only activation of astrocytes but also amyloidogenesis. In the cultured astrocytes, EGCG also inhibited LPS-induced cytokine release and amyloidogenesis. Thus, this study shows that EGCG prevents memory impairment as well as amyloidogenesis via inhibition of neuroinflammatory-related cytokines released from astrocytes and suggests that EGCG might be a useful intervention for neuroinflammation-associated AD. [Copyright &y& Elsevier]

Abstract: Neuroinflammation and accumulation of β-amyloid are critical pathogenic mechanisms of Alzheimer’s disease (AD). In the previous study, we have shown that systemic lipopolysaccharide (LPS) caused neuroinflammation with concomitant increase in β-amyloid and memory impairments in mice. In an attempt to investigate anti-neuroinflammatory properties of obovatol isolated from Magnolia obovata, we administered obovatol (0.2, 0.5 and 1.0mg/kg/day, p.o.) to animals for 21days before injection of LPS (0.25mg/kg, i.p.). We found that obovatol dose-dependently attenuates LPS-induced memory deficit in the Morris water maze and passive avoidance tasks. Consistent with the results of memory tasks, the compound prevented LPS-induced increases in Aβ1–42 formation, β- and γ-secretases activities and levels of amyloid precursor protein, neuronal β-secretase 1 (BACE1), and C99 (a product of BACE1) in the cortex and hippocampus. The LPS-mediated neuroinflammation as determined by Western blots and immunostainings was significantly ameliorated by the compound. Furthermore, LPS-induced nuclear factor (NF)-κB DNA binding activity was drastically abolished by obovatol as shown by the electrophoretic mobility shift assay. The anti-neuroinflammation and anti-amyloidogenesis by obovatol were replicated in in vitro studies. These results show that obovatol mitigates LPS-induced amyloidogenesis and memory impairment via inhibiting NF-κB signal pathway, suggesting that the compound might be plausible therapeutic intervention for neuroinflammation-related diseases such as AD. [Copyright &y& Elsevier]

Abstract: Oxidative stress induced neuronal cell death by accumulation of β-amyloid (Aβ) is a critical pathological mechanism of Alzheimer''s disease (AD). Intracerebroventrical infusion of Aβ1-42 (300 pmol/day per mouse) for 14 days induced neuronal cell death and memory impairment, but pre-treatment of 4-O-methylhonokiol (4-O-MH), a novel compound extracted from Magnolia officinalis for 3 weeks (0.2, 0.5 and 1.0 mg/kg) prior to the infusion of Aβ1-42 and during the infusion dose dependently improved Aβ1-42-induced memory impairment and prevented neuronal cell death. Additionally, 4-O-MH reduced Aβ1-42 infusion-induced oxidative damages of protein and lipid but reduced glutathione levels in the cortex and hippocampus. Aβ1-42 infusion-induced activation of astrocytes and p38 mitogenic activated protein (MAP) kinase was also prevented by 4-O-MH in mice brains. In further study using culture cortical neurons, p38 MAP kinase inhibitor abolished the inhibitory effect of 4-O-MH (10 μM) on the Aβ1-42 (5 μM)-induced reactive oxidative species generation and neuronal cell death. These results suggest that 4-O-MH might prevent the development and progression of AD through the reduction of oxidative stress and neuronal cell death via inactivation of p38 MAP kinase pathway. [Copyright &y& Elsevier]

Abstract: The bark and/or seed cones of the Magnolia tree have been used in traditional herbal medicines in Korea, China and Japan. Bioactive ingredients such as magnolol, honokiol, 4-O-methylhonokiol and obovatol have received great attention, judging by the large number of investigators who have studied their pharmacological effects for the treatment of various diseases. Recently, many investigators reported the anti-cancer, anti-stress, anti-anxiety, anti-depressant, anti-oxidant, anti-inflammatory and hepatoprotective effects as well as toxicities and pharmacokinetics data, however, the mechanisms underlying these pharmacological activities are not clear. The aim of this study was to review a variety of experimental and clinical reports and, describe the effectiveness, toxicities and pharmacokinetics, and possible mechanisms of Magnolia and/or its constituents. [Copyright &y& Elsevier]

Abstract: Presenilin 2 (PS2) mutation increases Aβ generation and neuronal cell death in the brains of Alzheimer disease (AD) patients. In a previous study, we showed that increased oxidative damage and activation of extracellular signal-regulated kinase (ERK) were associated with Aβ generation and neuronal cell death in neuronal cells expressing mutant PS2. In this study, we show that oral treatment with 4-O-methylhonokiol, a novel compound isolated from Magnolia officinalis, for 3months (1.0mg/kg) prevented PS2 mutation-induced memory impairment and neuronal cell death accompanied by a reduction in Aβ1-42 accumulation. We also found that 4-O-methylhonokiol inhibited PS2 mutation-induced activation of ERK and β-secretase, and oxidative protein and lipid damage, but recovered glutathione levels in the cortex and hippocampus of PS2 mutant mice. Additionally, 4-O-methylhonokiol prevented PS2 mutation-induced activation of astrocytes as well as production of TNF-α, IL-1β, reactive oxygen species (ROS), and nitric oxide (NO) in neurons. Generation of TNF-α, IL-1β, ROS, and NO and ERK activation in cultured astrocytes treated with lipopolysaccharide (1μg/ml) were also prevented by 4-O-methylhonokiol in a dose-dependent manner. These results suggest that the improving effects of 4-O-methylhonokiol on memory function may be associated with a suppression of the activation of ERK and astrocytes as well as a reduction in oxidative damage. Thus, 4-O-methylhonokiol may be useful in the prevention and treatment of AD. [ABSTRACT FROM AUTHOR]

Abstract: Amyloid β (Aβ)-induced neurotoxicity is a major pathological mechanism of Alzheimer disease (AD). In this study, we investigated the inhibitory effect of l-theanine, a component of green tea (Camellia sinensis), on Aβ1-42-induced neuronal cell death and memory impairment. Oral treatment of l-theanine (2 and 4 mg/kg) for 5 weeks in the drinking water of mice, followed by injection of Aβ1-42 (2 μg/mouse, icv), significantly attenuated Aβ1-42-induced memory impairment. Furthermore, l-theanine reduced Aβ1-42 levels and the accompanying Aβ1-42-induced neuronal cell death in the cortex and hippocampus of the brain. Moreover, l-theanine inhibited Aβ1-42-induced extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase as well as the activity of nuclear factor κB (NF-κB). l-Theanine also significantly reduced oxidative protein and lipid damage and the elevation of glutathione levels in the brain. These data suggest that the positive effects of l-theanine on memory may be mediated by suppression of ERK/p38 and NF-κB as well as the reduction of macromolecular oxidative damage. Thus, l-theanine may be useful in the prevention and treatment of AD. [Copyright &y& Elsevier]

Abstract: Activation of astrocytes has been known to be associated with amyloid-beta (Aβ) deposit and production of pro-inflammatory cytokines and chemokines that lead to neuronal cell death in the pathogenesis of Alzheimer disease (AD). In the present study, we investigated whether the absence of CC chemokine receptor 5 (CCR5) results in activation of astrocytes, Aβ deposit and memory dysfunction in CCR5 knock (CCR5−/−) out mice. We found that long-term and spatial memory functions were impaired in CCR5−/− mice. There was a significant increased expression of glial fibrillary acidic protein (GFAP) in the brain of CCR5−/− mice as compared with that of wild type of CCR5 (CCR5+/+) mice. The expression of CCR5 was observed in CCR5+/+ astrocytes, but was reduced in the CCR5−/− astrocytes even though the expression of GFAP was much higher. Paralleling with the activation of astorcytes, the Aβ1−42 level was higher in the brains of CCR5−/− mice than that of CCR5+/+ mice. Expression of β-secretase (BACE1) and its product C99 was significantly elevated in CCR5−/− mice. The activation of CC chemokine receptor 2 (CCR2) causes activation of astrocytes that leads to Aβ deposit and memory dysfunction in CCR5−/− mice. In CCR5−/− mice, CCR2 expression was high and co-localized with GFAP. These findings suggest that the absence of CCR5 increases expression of CCR2, which leads to the activation of astrocytes causing Aβ deposit, and thereby impairs memory function. These results suggest that CCR5 may be a critical suppressor of the development and progression of AD pathology. [Copyright &y& Elsevier]