Activation of the hypothalamo-anterior pituitary corticotropin-releasing hormone,adrenocorticotropin hormone and β-endorphin systems during the estradiol 17β-induced plasma LH surge in the ovariectomized monkey

The present work describes time-dependent changes in the content of corticotropin-releasing hormone (CRH), adrenocorticotropin (ACTH), and β-endorphin (β -EP) in the hypothalamus (HT) and anterior pituitary (AP) and in the concentration of ACTH and β-EP in the plasma during the 17β estradiol (E2) benzoate (E₂B)-induced luteinizing hormone (LH) surge in ovariectomized cynomolgus monkeys. Monkeys were euthanized at 0, 30, 48, 72, and 96 hr post-E₂B. HT and AP were rapidly dissected, extracted in 2 N acetic acid containing 1 mM phenylmethane sulfonyl fluoride at 4°C, and centrifuged at 18,000g for 30 min. Peptide concentrations were measured in the supernatant by specific radioimmunoassays (RIAs). In the HT, there were significant (P < 0.05) decreases in ACTH and β -EP content by 30 hr post-E₂B and a significant (P < 0.05) decrease in HT CRH content 48 hr post-E₂B. Thereafter, CRH, ACTH, and β-EP content increased up to 72 hr post-E₂B. In the AP, there was an almost linear decrease in the CRH content through 48 hr post-E₂B followed by a marked 20-fold (P< 0.01) increase in the AP CRH content at 72 hr post-E₂B, which corresponds to the time of the descending arm of the LH surge. The patterns of ACTH and β-EP content were very similar in the AP, while that of CRH differed markedly. In contrast, in the HT CRH, ACTH, and β-EP profiles were very similar. Significant (P< 0.05) increases in circulating levels of ACTH, β-EP, and cortisol were evident at 30 hr (all 3 hormones), 48 hr (β-EP and cortisol), and 72 hr (cortisol) post-E₂B, which corresponds with the time of decreased hypothalamic content of CR1I, ACTH, and β-EP. These results suggest that there may be a marked activation of the hypothalamo-anterior pituitary-adrenal axis during the negative and positive feedback phases of the E₂B-induced LH surge in the ovariectomized monkey. © 1995 Wiley-Liss, Inc.     

IL‐1β enhances the antibacterial activity of astrocytes by activation of NF‐κB

Astrocytes have important immune functions in CNS, and astrocytes stimulated by interferon‐γ were showed to have direct antimicrobial function. However whether astrocytes without the stimulation of cytokines have antibacterial function, and how this function is regulated are still largely unknown. In this study, we found that primary cultured astrocytes inhibited the growth of both gram‐negative and gram‐positive bacteria. Further more, we showed that interleukin‐1β (IL‐1β) enhanced the antibacterial effect in a dose‐dependent manner, and the antibacterial effect of astrocytes from IL‐1β receptor‐deficient mice failed to be enhanced by IL‐1β. IL‐1β stimulated IκBα degradation, NF‐κB nuclear translocation, and transactivation in astrocytes. NF‐κB inhibitors blocked NF‐κB activation and the enhanced antibacterial effect induced by IL‐1β. In addition, overexpression of dominant negative IκBα in astrocytes inhibited IκBα degradation and NF‐κB transactivation, and also inhibited the enhanced antibacterial effect induced by IL‐1β. All these data demonstrated that IL‐1β enhanced the antibacterial activity of astrocytes by activation of NF‐κB. © 2009 Wiley‐Liss, Inc.     

Enhanced aggregation and β structure of amyloid β peptide after coincubation with C1Q

Several lines of evidence now suggest that aggregation of soluble amyloid β peptide (Aβ) into a cross β sheet configuration may be an important factor in mediating potential neurotoxicity of Aβ. Synthetic Aβ has been shown to self aggregate in vitro. Here, we demonstrate that coincubation of freshly solubilized Aβ with C1q, a complement component known to bind Aβ in vitro and to colocalize with Aβ in vivo, results in as much as a 7-fold enhancement of Aβ aggregation, as well as a 2–4-fold enhancement of β structure within aggregates. The addition of C1q to preformed Aβ aggregates also results in significantly increased resistance to aggregate resolubilization. © 1994 Wiley-Liss, Inc.     

Implication of Akt‐dependent Prp19α/14‐3‐3β/Cdc5L complex formation in neuronal differentiation

PRP19α and CDC5L are major components of the active spliceosome. However, their association process is still unknown. Here, we demonstrated that PRP19α/14‐3‐3β/CDC5L complex formation is regulated by Akt during nerve growth factor (NGF)‐induced neuronal differentiation of PC12 cells. Analysis of PRP19α mutants revealed that the phosphorylation of PRP19α at Thr 193 by Akt was critical for its binding with 14‐3‐3β to translocate into the nuclei and for PRP19α/14‐3‐3β/CDC5L complex formation in neuronal differentiation. Forced expression of either sense PRP19α or sense 14‐3‐3β RNAs promoted NGF‐induced neuronal differentiation, whereas down‐regulation of these mRNAs showed a suppressive effect. The nonphosphorylation mutant PRP19αT193A lost its binding ability with 14‐3‐3β and acted as a dominant‐negative mutant in neuronal differentiation. These results imply that Akt‐dependent phosphorylation of PRP19α at Thr193 triggers PRP19α/14‐3‐3β/CDC5L complex formation in the nuclei, likely to assemble the active spliceosome against neurogenic pre‐mRNAs. © 2010 Wiley‐Liss, Inc.     

Attenuation of β‐amyloid‐induced tauopathy via activation of CK2α/SIRT1: Targeting for cilostazol

β‐Amyloid (Aβ) deposits and hyperphosphorylated tau aggregates are the chief hallmarks in the Alzheimer's disease (AD) brains, but the strategies for controlling these pathological events remain elusive. We hypothesized that CK2‐coupled SIRT1 activation stimulated by cilostazol suppresses tau acetylation (Ac‐tau) and tau phosphorylation (P‐tau) by inhibiting activation of P300 and GSK3β. Aβ was endogenously overproduced in N2a cells expressing human APP Swedish mutation (N2aSwe) by exposure to medium containing 1% fetal bovine serum for 24 hr. Increased Aβ accumulation was accompanied by increased Ac‐tau and P‐tau levels. Concomitantly, these cells showed increased P300 and GSK3β P‐Tyr216 expression; their expressions were significantly reduced by treatment with cilostazol (3–30 μM) and resveratrol (20 μM). Moreover, decreased expression of SIRT1 and its activity by Aβ were significantly reversed by cilostazol as by resveratrol. In addition, cilostazol strongly stimulated CK2α phosphorylation and its activity, and then stimulated SIRT1 phosphorylation. These effects were confirmed by using the pharmacological inhibitors KT5720 (1 μM, PKA inhibitor), TBCA (20 μM, inhibitor of CK2), and sirtinol (20 μM, SIRT1 inhibitor) as well as by SIRT1 gene silencing and overexpression techniques. In conclusion, increased cAMP‐dependent protein kinase‐linked CK2/SIRT1 expression by cilostazol can be a therapeutic strategy to suppress the tau‐related neurodegeneration in the AD brain. © 2013 Wiley Periodicals, Inc.     

Role of ERK map kinase and CRM1 in IL‐1β‐stimulated release of HMGB1 from cortical astrocytes

Reactive astrocytes are traditionally thought to impede brain plasticity after stroke. However, we previously showed that reactive astrocytes may also contribute to stroke recovery, partly via the release of a nuclear protein called high‐mobility group box 1 (HMGB1). Here, we investigate the mechanisms that allow stimulated astrocytes to release HMGB1. Exposure of rat primary astrocytes to IL‐1β for 24 h elicited a dose‐dependent HMGB1 response. Immunostaining and western blots of cell lysates showed increased intracellular levels of HMGB1. Western blots confirmed that IL‐1β induced a release of HMGB1 into astrocyte conditioned media. MAP kinase signaling was involved. Levels of phospho‐ERK were increased by IL‐1β, and the MEK/ERK inhibitor U0126 decreased HMGB1 upregulation in the stimulated astrocytes. Since HMGB1 is a nuclear protein, the role of the nuclear protein exporter, chromosome region maintenance 1 (CRM1), was assessed as a candidate mechanism for linking MAP kinase signaling to HMGB1 release. IL‐1β increased CRM1 expression in concert with a translocation of HMGB1 from nucleus into cytoplasm. Blockade of IL‐1β‐stimulated HMGB1 release with the ERK inhibitor U0126 was accompanied by a downregulation of CRM1. Our findings reveal that IL‐1β stimulates the release of HMGB1 from activated astrocytes via ERK MAP kinase and CRM1 signaling. These data suggest a novel pathway by which inflammatory cytokines may enhance the ability of reactive astrocytes to release prorecovery mediators after stroke. © 2010 Wiley‐Liss, Inc.     

Involvement of cathepsin B in the processing and secretion of interleukin‐1β in chromogranin A‐stimulated microglia

Cathepsin B (CB) is a cysteine lysosomal protease implicated in a number of inflammatory diseases. Although it is now evident that caspase‐1, an essential enzyme for maturation of interleukin‐1β (IL‐1β), can be activated through the inflammasome, there is still evidence suggesting the existence of lysosomal‐proinflammatory caspase pathways. In the present study, a marked induction of pro‐IL‐1β, its processing to the mature form and secretion were observed in the primary cultured microglia prepared from wild‐type mice after stimulation with chromogranin A (CGA). Although pro‐IL‐1β also markedly increased in microglia prepared from CB‐deficient mice, CB‐deficiency abrogated the pro‐IL‐1β processing. CA‐074Me, a specific inhibitor for CB, inhibited the pro‐IL‐1β maturation and its release from microglia. Furthermore, the caspase‐1 activation was also inhibited by CA‐074Me and E‐64d, a broad cysteine protease inhibitor. After treatment with CGA, CB was markedly induced at both protein and mRNA levels. The induced pro‐CB was rapidly processed to its mature form. The immunoreactivity for CB co‐localized with both that for caspase‐1 and the cleaved IL‐1β, in the acidic enlarged lysosomes. Inconsistent with these in vitro observations, the immunoreactivity for the cleaved IL‐1β was markedly observed in microglia of the hippocampus from aged wild‐type but not CB‐deficient mice. These observations strongly suggest that CB plays a key role in the pro‐IL‐1β maturationthrough the caspase‐1 activation in enlarged lysosomes ofCGA‐treated microglia. Therefore, either pharmacological or genetic inhibition of CB may provide therapeutic intervention in inflammation‐associated neurological diseases. © 2009 Wiley‐Liss, Inc.     

Characterization of plasma β‐secretase (BACE1) activity and soluble amyloid precursor proteins as potential biomarkers for Alzheimer's disease

Reduction in cerebrospinal fluid (CSF) amyloid β42 (Aβ42) and elevation in total tau and phospho‐thr181 tau consistently differentiate between Alzheimer's disease (AD) and age‐matched control subjects. In contrast, CSF β‐site APP‐cleaving enzyme activity (BACE1) and soluble amyloid precursor proteins α and β (sAPPα and sAPPβ) are without consistent patterns in AD subjects. Plasma sampling is much easier, with fewer side effects, and is readily applied in primary care centers, so we have developed and validated novel plasma BACE activity, sAPPβ, and sAPPα assays and investigated their ability to distinguish AD from age‐matched controls. Plasma BACE activity assay was sensitive and specific, with signal being immunodepleted with a specific BACE1 antibody and inhibited with a BACE1‐specific inhibitor. Plasma sAPPβ and sAPPα assays were specific, with signal diluting linearly, immunodepleted with specific antibodies, and at background levels in APP knockout mice. In rhesus monkeys, BACE1 but not γ‐secretase inhibitor led to significant lowering of plasma sAPPβ with concurrent elevation of plasma sAPPα. AD subjects showed a significant increase in plasma BACE1 activity, sAPPβ, sAPPα, and Aβ42 (P < 0.001) compared with age‐matched controls. In conclusion, plasma BACE activity and sAPP endpoints provide novel investigative biomarkers for AD diagnosis and potential pharmacodynamic biomarkers for secretase inhibitor studies. © 2012 Wiley Periodicals, Inc.     

γ‐Secretase binding sites in aged and Alzheimer's disease human cerebrum: the choroid plexus as a putative origin of CSF Aβ

Deposition of β ‐amyloid (Aβ) peptides, cleavage products of β‐amyloid precursor protein (APP) by β‐secretase‐1 (BACE1) and γ‐secretase, is a neuropathological hallmark of Alzheimer's disease (AD). γ‐Secretase inhibition is a therapeutical anti‐Aβ approach, although changes in the enzyme's activity in AD brain are unclear. Cerebrospinal fluid (CSF) Aβ peptides are thought to derive from brain parenchyma and thus may serve as biomarkers for assessing cerebral amyloidosis and anti‐Aβ efficacy. The present study compared active γ‐secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored the possibility of Aβ production and secretion by the choroid plexus (CP). The specific binding density of [³H]‐L‐685,458, a radiolabeled high‐affinity γ‐secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with similar ages and post‐mortem delays. The CP in post‐mortem samples exhibited exceptionally high [³H]‐L‐685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin‐1 immunoreactivity, and β‐site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins and released Aβ40 and Aβ42 into the medium. Overall, our results suggest that γ‐secretase activity appears unaltered in the cerebrum in AD and is not correlated with regional amyloid plaque pathology. The CP appears to be a previously unrecognised non‐neuronal contributor to CSF Aβ, probably at reduced levels in AD.     

α‐Synuclein activates innate immunity but suppresses interferon‐γ expression in murine astrocytes

Glial activation and neuroinflammation contribute to pathogenesis of neurodegenerative diseases, linked to neuron loss and dysfunction. α‐Synuclein (α‐syn), as a metabolite of neuron, can induce microglia activation to trigger innate immune response. However, whether α‐syn, as well as its mutants (A53T, A30P, and E46K), induces astrocyte activation and inflammatory response is not fully elucidated. In this study, we used A53T mutant and wild‐type α‐syns to stimulate primary astrocytes in dose‐ and time‐dependent manners (0.5, 2, 8, and 20 μg/ml for 24 hr or 3, 12, 24, and 48 hr at 2 μg/ml), and evaluated activation of several canonical inflammatory pathway components. The results showed that A53T mutant or wild‐type α‐syn significantly upregulated mRNA expression of toll‐like receptor (TLR)2, TLR3, nuclear factor‐κB and interleukin (IL)‐1β, displaying a pattern of positive dose–effect correlation or negative time–effect correlation. Such upregulation was confirmed at protein levels of TLR2 (at 20 μg/ml), TLR3 (at most doses), and IL‐1β (at 3 hr) by western blotting. Blockage of TLR2 other than TLR4 inhibited TLR3 and IL‐1β mRNA expressions. By contrast, interferon (IFN)‐γ was significantly downregulated at mRNA, protein, and protein release levels, especially at high concentrations of α‐syns or early time‐points. These findings indicate that α‐syn was a TLRs‐mediated immunogenic agent (A53T mutant stronger than wild‐type α‐syn). The stimulation patterns suggest that persistent release and accumulation of α‐syn is required for the maintenance of innate immunity activation, and IFN‐γ expression inhibition by α‐syn suggests a novel immune molecule interaction mechanism underlying pathogenesis of neurodegenerative diseases.     

A genome‐wide association study‐derived polygenic score for interleukin‐1β is associated with hippocampal volume in two samples

Accumulating research suggests that the pro‐inflammatory cytokine interleukin‐1β (IL‐1β) has a modulatory effect on the hippocampus, a brain structure important for learning and memory as well as linked with both psychiatric and neurodegenerative disorders. Here, we used an imaging genetics strategy to test an association between an IL‐1β polygenic score and hippocampal volume in two independent samples. Our polygenic score was derived using summary statistics from a recent genome‐wide association study of circulating cytokines that included IL‐1β (N = 3,309). In the first sample of 512 non‐Hispanic Caucasian university students (274 women, mean age 19.78 ± 1.24 years) from the Duke Neurogenetics Study, we identified a significant positive correlation between IL‐1β polygenic scores and hippocampal volume. This positive association was successfully replicated in a second sample of 7,960 white British volunteers (4,158 women, mean age 62.63 ± 7.45 years) from the UK Biobank. Our results lend further support in humans, to the link between IL‐1β and the structure of the hippocampus.     

A critical role of TRPM2 channel in Aβ42‐induced microglial activation and generation of tumor necrosis factor‐α

Amyloid β (Aβ)‐induced neuroinflammation plays an important part in Alzheimer's disease (AD). Emerging evidence supports a role for the transient receptor potential melastatin‐related 2 (TRPM2) channel in Aβ‐induced neuroinflammation, but how Aβ induces TRPM2 channel activation and this relates to neuroinflammation remained poorly understood. We investigated the mechanisms by which Aβ₄₂ activates the TRPM2 channel in microglial cells and the relationships to microglial activation and generation of tumor necrosis factor‐α (TNF‐α), a key cytokine implicated in AD. Exposure to 10–300 nM Aβ₄₂ induced concentration‐dependent microglial activation and generation of TNF‐α that were ablated by genetically deleting (TRPM2 knockout ;TRPM2‐KO) or pharmacologically inhibiting the TRPM2 channel, revealing a critical role of this channel in Aβ₄₂‐induced microglial activation and generation of TNF‐α. Mechanistically, Aβ₄₂ activated the TRPM2 channel via stimulating generation of reactive oxygen species (ROS) and activation of poly(ADPR) polymerase‐1 (PARP‐1). Aβ₄₂‐induced generation of ROS and activation of PARP‐1 and TRPM2 channel were suppressed by inhibiting protein kinase C (PKC) and NADPH oxidases (NOX). Aβ₄₂‐induced activation of PARP‐1 and TRPM2 channel was also reduced by inhibiting PYK2 and MEK/ERK. Aβ₄₂‐induced activation of PARP‐1 was attenuated by TRPM2‐KO and moreover, the remaining PARP‐1 activity was eliminated by inhibiting PKC and NOX, but not PYK2 and MEK/ERK. Collectively, our results suggest that PKC/NOX‐mediated generation of ROS and subsequent activation of PARP‐1 play a role in Aβ₄₂‐induced TRPM2 channel activation and TRPM2‐dependent activation of the PYK2/MEK/ERK signalling pathway acts as a positive feedback to further facilitate activation of PARP‐1 and TRPM2 channel. These findings provide novel insights into the mechanisms underlying Aβ‐induced AD‐related neuroinflammation.     

Differential effects of morphine withdrawal on cerebral β1- and β2-adrenergic receptors

Effect of morphine dependence and its withdrawal on the ³H-dihydroalprenolol (³H-DHA) binding for βadrenergic receptors,β₁ andβ₂, was examined by a computerized analysis of biphasic Hofstee plots. The relative density ofβ₁ andβ₂ receptors in the rat cerebral cortex was found to be approximately 70% and 30%, respectively. In rats rendered dependent on morphine by a subcutaneous implantation of a morphine pellet, the ³H-DHA binding toβ₁ andβ₂ receptors was not altered. During the stage of withdrawal induced by administration of naloxone, however, the ³H-DHA binding to the cerebral particulate fractions was increased, and this increase was due to the increased binding sites inβ₁ but not inβ₂ receptor. On the other hand, the apparent affinities ofβ₁ andβ₂ receptors for atenolol and salbutamol, selective antagonists forβ₁- andβ₂-adrenergic receptors, respectively, were not altered under these experimental conditions. These results suggest that an abrupt increase in cerebralβ₁-receptor binding sites occurs at morphine withdrawal, and the occurrence of such a supersensitivity in cerebralβ₁ receptor may be involved in the exhibition and/or maintenance of the abstinence syndrome in morphine-dependent subjects.     

Minocycline and fluorocitrate suppress spinal nociceptive signaling in intrathecal IL‐1β–induced thermal hyperalgesic rats

We previously demonstrated that intrathecal IL‐1β caused thermal hyperalgesia in rats. This study was conducted to examine the effects and cellular mechanisms of glial inhibitors on IL‐1β–induced nociception in rats. The effects of minocycline (20 μg), fluorocitrate (1 nmol), and SB203580 (5 μg) on IL‐1β (100 ng) treatment in rats were measured by nociceptive behaviors, western blotting of p38 mitogen‐activated protein kinase (MAPK) and inducible nitric oxide synthase (iNOS) expression, cerebrospinal fluid nitric oxide (NO) levels, and immunohistochemical analyses. The results demonstrated that intrathecal IL‐1β activated microglia and astrocytes, but not neurons, in the dorsal horn of the lumbar spinal cord, as evidenced by morphological changes and increased immunoreactivity, phosphorylated p38 (P‐p38) MAPK, and iNOS expression; the activation of microglia and astrocytes peaked at 30 min and lasted for 6 h. The immunoreactivities of microglia and astrocytes were significantly increased at 30 min (6.6‐ and 2.7‐fold, respectively) and 6 h (3.3‐ and 4.0‐fold, respectively) following IL‐1β injection, as compared with saline controls at 30 min (all P < 0.01). IL‐1β induced P‐p38 MAPK and iNOS expression predominantly in microglia and less in astrocytes. Minocycline, fluorocitrate, or SB203580 pretreatment suppressed this IL‐1β–upregulated P‐p38 MAPK mainly in microglia and iNOS mainly in astrocytes; minocycline exhibited the most potent effect. Minocycline and fluorocitrate pretreatment abrogated IL‐1β–induced NO release and thermal hyperalgesia in rats. In conclusion, minocycline, fluorocitrate, and SB203580 effectively suppressed the IL‐1β–induced central sensitization and hyperalgesia in rats. © 2012 Wiley Periodicals, Inc.     

Pro-opiocortin fragments in human and rat brain: β-endorphin and α-MSH are the predominant peptides

The ‘pro-opiocortin’ fragments, β-lipotropin, β-endorphin, ACTH and α-MSH, were estimated in discrete areas of rat and human brain and pituitaries by means of radioimmunoassay in combination with gelfiltration. These peptides exihibited parallel patterns of distribution, but with β-endorphin and α-MSH predominant in the brain of rat and man, and, in contrast, their respective precursors, β-LPH and ACTH predominant in the adenohypophysis of rat and man. These data may be indicative of important differences in post-translational processing of ‘pro-opiocortin’ between these contrasting tissues.     

Tyrosine phosphatase STEP61 negatively regulates amyloid β‐mediated ERK/CREB signaling pathways via α7 nicotinic acetylcholine receptors

Striatal‐enriched phosphatase 61 (STEP₆₁) plays an essential role in synaptic plasticity and has recently been implicated in neurodegenerative disease. Here we characterized a possible role of STEP₆₁ in Alzheimer's disease (AD) pathology using a mouse model of AD (Tg‐APPswe/PSEN1dE9, APP/PS1 mice) and an in vitro model of AD [cortical neurons treated with amyloid β (Aβ)_1–42 peptides]. Our data indicate age‐related elevation of STEP₆₁ levels and the proportion of dephosphorylated STEP₆₁ (active STEP₆₁) in wild‐type mice, which was enhanced in APP/PS1 mice. Furthermore, the increased STEP₆₁ levels and active STEP₆₁ were observed in the hippocampus and cortex from 12‐month‐old APP/PS1 mice and in Aβ_1–42‐treated cortical neurons. An α7 nicotinic acetylcholine receptors (nAChRs) antagonist, α‐bungarotoxin (BTX), inhibited the Aβ_1–42‐induced increase of STEP₆₁ expression and activation. In addition, extracellular signal‐regulated kinase 1/2 (ERK1/2) and cAMP response element binding (CREB) were impaired in Aβ_1–42‐treated cortical neurons, and knockdown of STEP₆₁ enhanced the activation of ERK1/2 and CREB. Collectively, these findings indicate two alternate pathological pathways effecting STEP₆₁ regulation in AD. First, Aβ regulating STEP₆₁ activity is mediated by Aβ binding to α7 nAChRs. Second, STEP₆₁ negatively regulates Aβ‐mediated ERK/CREB pathway, an important signaling cascade involved in memory formation. © 2013 Wiley Periodicals, Inc.     

β-amyloid binds to p75NTR and activates NFκB in human neuroblastoma cells

Amyloid β peptide (Aβ), a proteolytic fragment of the amyloid precursor protein (APP), is a major component of the plaques found in the brain of Alzheimer's disease (AD) patients. These plaques are thought to cause the observed loss of cholinergic neurons in the basal forebrain of AD patients. In these neurons, particularly those of the nucleus basalis of Meynert, an up-regulation of 75kD-neurotrophin receptor (p75^NTR), a nonselective neurotrophin receptor belonging to the death receptor family, has been reported. p75^NTR expression has been described to correlate with β-amyloid sensitivity in vivo and in vitro, suggesting a possible role for p75^NTR as a receptor for Aβ. Here we used a human neuroblastoma cell line to investigate the involvement of p75^NTR in Aβ-induced cell death. Aβ peptides were found to bind to p75^NTR resulting in activation of NFκB in a time- and dose-dependent manner. Blocking the interaction of Aβ with p75^NTR using NGF or inhibition of NFκB activation by curcumin or NFκB SN50 attenuated or abolished Aβ-induced apoptotic cell death. The present results suggest that p75^NTR might be a death receptor for Aβ, thus being a possible drug target for treatment of AD. J. Neurosci. Res. 54:798–804, 1998. © 1998 Wiley-Liss, Inc.     

Relative efficacies of amyloid β peptide (Aβ) binding proteins in Aβ aggregation

The aggregation of amyloid β peptide (Aβ) into its fibrillar, cross β-pleated configuration is generally viewed as a critical event in the pathophysiology of Alzheimer's disease (AD). A diverse group of molecules, the Aβ binding proteins, has been evaluated for their effects on this process. However, most of these studies have used micromolar or greater reagent concentrations, and their different methods have not permitted quantitative comparisons of the efficacy of different Aβ binding proteins in augmenting or inhibiting aggregation. In the present work we have undertaken a coherent analysis using fluorimetry of thioflavin T-stained experimental solutions. The complement protein C1q, serum amyloid P, and transthyretin significantly enhanced the formation of precipitable, cross β-pleated aggregates in solutions of 800 nM Aβ1–42. Under these same experimental conditions, α₁-antichymotrypsin had no significant effect on the aggregation process, and both the E3 and E4 isoforms of apolipoprotein E were significant inhibitors. There was a non-significant trend toward the E3 isoform exhibiting greater inhibition than the E4 isoform. Of the aggregation-facilitating molecules, C1q was substantially and significantly the most potent. © 1996 Wiley-Liss, Inc.