NIH PubMed latest 50 research articles on Alzheimer's

Protease inhibitors: A panacea?

Haq SK, Rabbani G, Ahmad E, Atif SM, Khan RH

Protease inhibitors: A panacea?

J Biochem Mol Toxicol. 2010 Feb 4;

Authors: Haq SK, Rabbani G, Ahmad E, Atif SM, Khan RH

With the increasing evidence of protease involvement in several diseases, novel strategies for drug development involve the use of protease inhibitors (PIs). The local balance between protease inhibitors and proteases is an important determinant of the occurrence and progression of a particular disease. Hence, enzymes and their cognate inhibitors are finding their applications as diagnostic and prognostic markers. PIs are widely implicated for their use in host defense against infection, tissue repair and matrix production, blood coagulation, cancer, and they are, therefore, the current focus as therapeutic alternatives for major diseases such as AIDS and Alzheimer's diseases. This review is a brief summary of the varied role of protein protease inhibitors in controlling the activity of aberrant enzymes in several diseases afflicting mankind today. (c) 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 00:1-8, 2010; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20335.

PMID: 20135636 [PubMed - as supplied by publisher]

Vesicular monoamine transporters: Structure-function, pharmacology, and medicinal chemistry.

Wimalasena K

Vesicular monoamine transporters: Structure-function, pharmacology, and medicinal chemistry.

Med Res Rev. 2010 Feb 4;

Authors: Wimalasena K

Vesicular monoamine transporters (VMAT) are responsible for the uptake of cytosolic monoamines into synaptic vesicles in monoaminergic neurons. Two closely related VMATs with distinct pharmacological properties and tissue distributions have been characterized. VMAT1 is preferentially expressed in neuroendocrine cells and VMAT2 is primarily expressed in the CNS. The neurotoxicity and addictive properties of various psychostimulants have been attributed, at least partly, to their interference with VMAT2 functions. The quantitative assessment of the VMAT2 density by PET scanning has been clinically useful for early diagnosis and monitoring of the progression of Parkinson's and Alzheimer's diseases and drug addiction. The classical VMAT2 inhibitor, tetrabenazine, has long been used for the treatment of chorea associated with Huntington's disease in the United Kingdom, Canada, and Australia, and recently approved in the United States. The VMAT2 imaging may also be useful for exploiting the onset of diabetes mellitus, as VMAT2 is also expressed in the beta-cells of the pancreas. VMAT1 gene SLC18A1 is a locus with strong evidence of linkage with schizophrenia and, thus, the polymorphic forms of the VMAT1 gene may confer susceptibility to schizophrenia. This review summarizes the current understanding of the structure-function relationships of VMAT2, and the role of VMAT2 on addiction and psychostimulant-induced neurotoxicity, and the therapeutic and diagnostic applications of specific VMAT2 ligands. The evidence for the linkage of VMAT1 gene with schizophrenia and bipolar disorder I is also discussed. (c) 2010 Wiley Periodicals, Inc. Med Res Rev.

PMID: 20135628 [PubMed - as supplied by publisher]

An enzyme-linked immunosorbent assay to compare the affinity of chemical compounds for beta-amyloid peptide as a monomer.

Jiang C, Feng Y, Huang X, Xu Y, Zhang Y, Zhou N, Shen X, Chen K, Jiang H, Liu D

An enzyme-linked immunosorbent assay to compare the affinity of chemical compounds for beta-amyloid peptide as a monomer.

Anal Bioanal Chem. 2010 Feb 6;

Authors: Jiang C, Feng Y, Huang X, Xu Y, Zhang Y, Zhou N, Shen X, Chen K, Jiang H, Liu D

Abeta(1-42) is the proteolytic cleavage product of cleavage of the amyloid precursor protein by beta- and gamma-secretases. The aggregation of Abeta(1-42) plays a causative role in the development of Alzheimer's disease. To lock Abeta(1-42) in a homogenous state, we embedded the Abeta(1-42) sequence in an unstructured region of Bcl-x(L). Both the N-terminus and the C-terminus of Abeta(1-42) were constrained in the disordered region, whereas the conjunction did not introduce any folding to Abeta(1-42) but maintained the sequence as a monomer in solution. With Bcl-x(L)-Abeta(42), we developed an enzyme-linked immunosorbent assay to compare the affinity of compounds for monomeric Abeta(1-42). Bcl-x(L)-Abeta(42) was coated on a microplate and this was followed by incubation with different concentrations of compounds. Compounds binding to Leu17-Val24 of Abeta(1-42) inhibited the interaction between Bcl-x(L)-Abeta(42) and antibody 4G8. The method can not only reproduce the activities of the reported Abeta(1-42) inhibitors such as dopamine, tannin, and morin but can also differentiate decoy compounds that do not bind to Abeta(1-42). Remarkably, using this method, we discovered a new inhibitor that binds to monomeric Abeta(1-42) and inhibits Abeta(1-42) fibril formation. As the structure of Bcl-x(L)-Abeta(42) monomer is stable in solution, the assay could be adapted for high-throughput screening with a series of antibodies that bind the different epitopes of Abeta(1-42). In addition, the monomeric form of the Abeta(1-42) sequence in Bcl-x(L)-Abeta(42) would also facilitate the identification of Abeta(1-42) binding partners by coimmunoprecipitation, cocrystallization, surface plasmon resonance technology, or the assay as described here.

PMID: 20135308 [PubMed - as supplied by publisher]

Association of phosphatidylcholine and NSAIDs as a novel strategy to reduce gastrointestinal toxicity.

Lichtenberger LM, Barron M, Marathi U

Association of phosphatidylcholine and NSAIDs as a novel strategy to reduce gastrointestinal toxicity.

Drugs Today (Barc). 2009 Dec;45(12):877-90

Authors: Lichtenberger LM, Barron M, Marathi U

Nonsteroidal anti-inflammatory drugs (NSAIDs) are highly effective drugs that inhibit pain and inflammation, and perhaps due to the role of inflammation in the underlying etiology, NSAIDs have also demonstrated efficacy in reducing a patient's risk of developing a number of cancers and neurological diseases (e.g. Alzheimer's disease). The utility of these powerful drugs is limited due to their gastrointestinal (GI) side-effects, notably peptic ulceration and GI bleeding which is briefly reviewed here. We also describe the barrier property of the GI mucosa and how it is affected by NSAIDs, as it is our position that disruption of the surface barrier is an important component in the drugs' pathogenesis, in addition to selective inhibition of COX-2, which has proven to be problematic. We also discuss current alternative approaches being taken to mitigate the GI side-effects of NSAIDs, including developing combination drugs where NSAIDs are packaged with inhibitors of HCl secretion such as proton pump inhibitors or H2-receptor antagonists. We then present the rationale for the development of the PC associated NSAID technology which came out of our observation that the mammalian gastric mucosa has hydrophobic, nonwettable properties that provides a barrier to luminal acid, and the role of phospholipids and specifically phosphatidylcholine (PC) in this barrier property. In the last section we review the development of our current lipid-based PC-NSAID formulations and our encouraging preclinical and clinical observations validating their GI safety and therapeutic efficacy.

PMID: 20135022 [PubMed - in process]

Neuroimmunomodulation in the Pathogenesis of Alzheimer's Disease.

Morales I, Farías G, Maccioni RB

Neuroimmunomodulation in the Pathogenesis of Alzheimer's Disease.

Neuroimmunomodulation. 2010;17(3):202-204

Authors: Morales I, Farías G, Maccioni RB

Evidence has been cumulated on the role of microglia cells deregulation and alterations in their interaction patterns with brain neurons, in the pathway towards neurodegeneration in Alzheimer's disease (AD). After the failure of the amyloid hypothesis to explain AD pathogenesis, current hypotheses focus on tau self-polymerization into pathological oligomers and filaments as a major culprit for neurofibrillary degeneration. It is worth pointing out that formation of tau polymers is consistent with the clinical and neuropathological observations, and that tangles are pathognomonic of AD and related tau disorders. In this context, inflammatory processes play a major role in neuronal degeneration. On the basis of studies on microglia and neuronal cultures, together with experiments in animal models, and the clinical evidence, we postulated that a series of endogenous damage signals activate microglia cells, inducing NFkappa-beta with the consequent release of cytokine mediators such as TNF-alpha, IL-6 and IL-1beta. An overexpression of these mediators may trigger signaling cascades in neurons leading to activation of protein kinases gsk3beta, cdk5, abl kinases, along with inactivation of phosphatases such as PP1, with the resulting hyperphosphorylation and self-aggregation of tau protein into neurotoxic oligomeric species.

PMID: 20134203 [PubMed - as supplied by publisher]

Synthetic amyloid-{beta} oligomers impair long-term memory independently of cellular prion protein.

Synthetic amyloid-{beta} oligomers impair long-term memory independently of cellular prion protein.

Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2295-300

Authors: Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T, Chiesa R, Gobbi M, Salmona M, Forloni G

Inability to form new memories is an early clinical sign of Alzheimer's disease (AD). There is ample evidence that the amyloid-beta (Abeta) peptide plays a key role in the pathogenesis of this disorder. Soluble, bio-derived oligomers of Abeta are proposed as the key mediators of synaptic and cognitive dysfunction, but more tractable models of Abeta-mediated cognitive impairment are needed. Here we report that, in mice, acute intracerebroventricular injections of synthetic Abeta(1-42) oligomers impaired consolidation of the long-term recognition memory, whereas mature Abeta(1-42) fibrils and freshly dissolved peptide did not. The deficit induced by oligomers was reversible and was prevented by an anti-Abeta antibody. It has been suggested that the cellular prion protein (PrP(C)) mediates the impairment of synaptic plasticity induced by Abeta. We confirmed that Abeta(1-42) oligomers interact with PrP(C), with nanomolar affinity. However, PrP-expressing and PrP knock-out mice were equally susceptible to this impairment. These data suggest that Abeta(1-42) oligomers are responsible for cognitive impairment in AD and that PrP(C) is not required.

PMID: 20133875 [PubMed - in process]

Mechanism of amyloid plaque formation suggests an intracellular basis of A{beta} pathogenicity.

Mechanism of amyloid plaque formation suggests an intracellular basis of A{beta} pathogenicity.

Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):1942-7

Authors: Friedrich RP, Tepper K, Rönicke R, Soom M, Westermann M, Reymann K, Kaether C, Fändrich M

The formation of extracellular amyloid plaques is a common patho-biochemical event underlying several debilitating human conditions, including Alzheimer's disease (AD). Considerable evidence implies that AD damage arises primarily from small oligomeric amyloid forms of Abeta peptide, but the precise mechanism of pathogenicity remains to be established. Using a cell culture system that reproducibly leads to the formation of Alzheimer's Abeta amyloid plaques, we show here that the formation of a single amyloid plaque represents a template-dependent process that critically involves the presence of endocytosis- or phagocytosis-competent cells. Internalized Abeta peptide becomes sorted to multivesicular bodies where fibrils grow out, thus penetrating the vesicular membrane. Upon plaque formation, cells undergo cell death and intracellular amyloid structures become released into the extracellular space. These data imply a mechanism where the pathogenic activity of Abeta is attributed, at least in part, to intracellular aggregates.

PMID: 20133839 [PubMed - in process]

A role for FKBP52 in Tau protein function.

A role for FKBP52 in Tau protein function.

Proc Natl Acad Sci U S A. 2010 Jan 25;

Authors: Chambraud B, Sardin E, Giustiniani J, Dounane O, Schumacher M, Goedert M, Baulieu EE

Tau is a microtubule-associated protein, which is widely expressed in the central nervous system, predominantly in neurons, where it regulates microtubule dynamics, axonal transport, and neurite outgrowth. The aberrant assembly of Tau is the hallmark of several human neurodegenerative diseases, collectively known as tauopathies. They include Alzheimer's disease, Pick's disease, progressive supranuclear palsy, and frontotemporal dementia and parkinsonism linked to chromosome 17. Several abnormalities in Tau, such as hyperphosphorylation and aggregation, alter its function and are central to the pathogenic process. Here, we describe biochemical and functional interactions between FKBP52 and Tau. FKBP52 is a member of the FKBP (FK506-binding protein) family that comprises intracellular protein effectors of immunosuppressive drugs (such as FK506 and rapamycin). We found that FKBP52, which is abundant in brain, binds directly and specifically to Tau, especially in its hyperphosphorylated form. The relevance of this observation was confirmed by the colocalization of both proteins in the distal part of the axons of cortical neurons and by the antagonistic effect of FKBP52 on the ability of Tau to promote microtubule assembly. Overexpression of FKBP52 in differentiated PC12 cells prevented the accumulation of Tau and resulted in reduced neurite length. Taken together, these findings indicate a role for FKBP52 in Tau function and may help to decipher and modulate the events involved in Tau-induced neurodegeneration.

PMID: 20133804 [PubMed - as supplied by publisher]

ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD.

ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD.

Proc Natl Acad Sci U S A. 2010 Jan 26;

Authors: Bryleva EY, Rogers MA, Chang CC, Buen F, Harris BT, Rousselet E, Seidah NG, Oddo S, Laferla FM, Spencer TA, Hickey WF, Chang TY

Cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative diseases, including the abnormal accumulation of amyloid-beta, one of the pathological hallmarks of Alzheimer disease (AD). Acyl-CoA:cholesterol acyltransferases (ACAT1 and ACAT2) are two enzymes that convert free cholesterol to cholesteryl esters. ACAT inhibitors have recently emerged as promising drug candidates for AD therapy. However, how ACAT inhibitors act in the brain has so far remained unclear. Here we show that ACAT1 is the major functional isoenzyme in the mouse brain. ACAT1 gene ablation (A1-) in triple transgenic (i.e., 3XTg-AD) mice leads to more than 60% reduction in full-length human APPswe as well as its proteolytic fragments, and ameliorates cognitive deficits. At 4 months of age, A1- causes a 32% content increase in 24-hydroxycholesterol (24SOH), the major oxysterol in the brain. It also causes a 65% protein content decrease in HMG-CoA reductase (HMGR) and a 28% decrease in sterol synthesis rate in AD mouse brains. In hippocampal neurons, A1- causes an increase in the 24SOH synthesis rate; treating hippocampal neuronal cells with 24SOH causes rapid declines in hAPP and in HMGR protein levels. A model is provided to explain our findings: in neurons, A1- causes increases in cholesterol and 24SOH contents in the endoplasmic reticulum, which cause reductions in hAPP and HMGR protein contents and lead to amelioration of amyloid pathology. Our study supports the potential of ACAT1 as a therapeutic target for treating certain forms of AD.

PMID: 20133765 [PubMed - as supplied by publisher]

No difference in kinetics of tau or histone phosphorylation by CDK5/p25 versus CDK5/p35 in vitro.

Peterson DW, Ando DM, Taketa DA, Zhou H, Dahlquist FW, Lew J

No difference in kinetics of tau or histone phosphorylation by CDK5/p25 versus CDK5/p35 in vitro.

Proc Natl Acad Sci U S A. 2010 Feb 1;

Authors: Peterson DW, Ando DM, Taketa DA, Zhou H, Dahlquist FW, Lew J

CDK5/p35 is a cyclin-dependent kinase essential for normal neuron function. Proteolysis of the p35 subunit in vivo results in CDK5/p25 that causes neurotoxicity associated with a number of neurodegenerative diseases. Whereas the mechanism by which conversion of p35 to p25 leads to toxicity is unknown, there is common belief that CDK5/p25 is catalytically hyperactive compared to CDK5/p35. Here, we have compared the steady-state kinetic parameters of CDK5/p35 and CDK5/p25 towards both histone H1, the best known substrate for both enzymes, and the microtubule-associated protein, tau, a physiological substrate whose in vivo phosphorylation is relevant to Alzheimer's disease. We show that the kinetics of both enzymes are the same towards either substrate in vitro. Furthermore, both enzymes display virtually identical kinetics towards individual phosphorylation sites in tau monitored by NMR. We conclude that conversion of p35 to p25 does not alter the catalytic efficiency of the CDK5 catalytic subunit by using histone H1 or tau as substrates, and that neurotoxicity associated with CDK5/p25 is unlikely attributable to CDK5 hyperactivation, as measured in vitro.

PMID: 20133653 [PubMed - as supplied by publisher]

Phosphorylated tau 231, memory decline and medial temporal atrophy in normal elders.

Phosphorylated tau 231, memory decline and medial temporal atrophy in normal elders.

Neurobiol Aging. 2010 Feb 2;

Authors: Glodzik L, de Santi S, Tsui WH, Mosconi L, Zinkowski R, Pirraglia E, Wang HY, Li Y, Rich KE, Zetterberg H, Blennow K, Mehta P, de Leon MJ

Little is known whether cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) can predict both memory decline and associated longitudinal medial temporal lobe (MTL) gray matter (GM) reductions in cognitively healthy individuals. Fifty-seven normal elderly subjects received comprehensive evaluation at baseline and 2 years later. The baseline phosphorylated tau(231) (p-tau(231)), total tau, the amyloid beta (Abeta) Abeta42/Abeta40, t-tau/Abeta42 and p-tau(231)/Abeta42 ratios were examined as predictors of memory change and reductions in the global and MTL GM, determined from T1-weighted MRI. Twenty out of 57 participants experienced reduced memory performance at follow-up. The group with decreased memory performance showed higher baseline p-tau(231) (Z=-2.2, p=0.03), lower Abeta42/Abeta40 (t=-2.2 [55], p=0.04) and greater longitudinal MTL GM reductions (t([52])=-2.70, p=0.01). Higher baseline p-tau(231) was also associated with the absolute decrease in memory scores (rho=-0.30, p=0.02) and with longitudinal MTL GM reduction (F([2,52])=4.4, p=0.04, age corrected). Our results indicate that in normal individuals, elevated p-tau(231), a marker of neurofibrillary pathology is related to both a decrease in declarative memory and progressive atrophy of the MTL, suggesting its diagnostic potential in preclinical stage.

PMID: 20133017 [PubMed - as supplied by publisher]

Association of AICD and Fe65 with Hirano bodies reduces transcriptional activation and initiation of apoptosis.

Ha S, Furukawa R, Fechheimer M

Association of AICD and Fe65 with Hirano bodies reduces transcriptional activation and initiation of apoptosis.

Neurobiol Aging. 2010 Feb 2;

Authors: Ha S, Furukawa R, Fechheimer M

Hirano bodies are cytoplasmic inclusions predominantly found in the central nervous system associated with various conditions including aging and Alzheimer's disease (AD). Since most studies of Hirano bodies have been performed in post-mortem samples, the physiological roles of Hirano bodies have not been investigated. Astrocytoma H4 cells were employed to test the hypothesis that Hirano bodies interact with and modulate signaling by the C-terminal fragment of amyloid-beta precursor protein (AICD). We demonstrated by immunofluorescence and immunoprecipitation that model Hirano bodies accumulate AICD. Since stimulation of transcription by AICD is dependent on its interaction with the nuclear adaptor protein Fe65, we examined localization of Fe65, and employed a dual luciferase reporter assay to test the effects of Hirano bodies on AICD- and Fe65-dependent modulation of gene expression. We find that both AICD and Fe65 are co-localized in model Hirano bodies. Model Hirano bodies also down-regulate both AICD-dependent apoptosis and AICD- and Fe65-dependent transcriptional activity. Thus, association of AICD and Fe65 with Hirano bodies impedes their function in promoting apoptosis and modulating transcription.

PMID: 20133016 [PubMed - as supplied by publisher]

Is there a CSF biomarker profile related to depression in elderly women?

Is there a CSF biomarker profile related to depression in elderly women?

Psychiatry Res. 2010 Feb 2;

Authors: Gudmundsson P, Skoog I, Waern M, Blennow K, Zetterberg H, Rosengren L, Gustafson D

In light of our previous observation of higher levels of cerebrospinal fluid (CSF) amyloid beta-42 (Abeta42) and CSF/serum albumin ratio in major depressive disorder (MDD), we analyzed two additional CSF biomarkers reflecting neurodegeneration-neurofilament protein light (NFL) and glial fibrillary acidic protein (GFAp)-in relationship to prevalent geriatric depression. Neuropsychiatric, physical, and lumbar puncture examinations, with DSM-III-R-based depression diagnoses and measurement of CSF levels of NFL and GFAp, were evaluated among a population-based sample of 78 elderly women (mean age, 73.9+/-3.2 years) without dementia for at least 10 years after CSF collection. Eleven (13.1%) women had MDD, and higher levels of NFL compared with women without depression. A multivariate model including age, NFL, Abeta42 and the CSF/serum albumin ratio showed that each biomarker was independently and positively associated with MDD, and that this biomarker profile explained more variation in the model compared with single or combined biomarkers. A CSF profile with higher levels of NFL, Abeta42, and CSF/serum albumin ratio may indicate neuropathological and vascular events in depression etiology. This contrasts with the well-characterized pattern of low Abeta42, higher CSF/serum albumin ratio, and higher NFL in Alzheimer's disease.

PMID: 20132991 [PubMed - as supplied by publisher]

SLV330, a cannabinoid CB(1) receptor antagonist, ameliorates deficits in the T-maze, object recognition and social recognition tasks in rodents.

SLV330, a cannabinoid CB(1) receptor antagonist, ameliorates deficits in the T-maze, object recognition and social recognition tasks in rodents.

Neurobiol Learn Mem. 2010 Feb 1;

Authors: Bruin NM, Prickaerts J, Lange JH, Akkerman S, Andriambeloson E, Haan MD, Wijnen J, Drimmelen MV, Hissink E, Heijink L, Kruse CG

Cannabinoid CB(1) receptor (CB(1)R) signaling has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the CB(1)R antagonist SLV330 (doses ranging from 0.3-10mg/kg, given orally, p.o.) could ameliorate impairments in distinct aspects of cognition using different disruption models in both mice and rats. Effects of SLV330 were tested on working memory deficits in the T-maze Continuous Alternation Task (T-CAT) in mice; episodic memory deficits in the Object Recognition Task (ORT) and Social Recognition Task (SRT) in rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept(R), approved for symptomatic treatment of Alzheimer's disease) and nicotine were used as reference compounds. SLV330 markedly improved aging and scopolamine -induced memory deficits in the T-CAT in mice with a lowest effective dose (LED) of 1mg/kg p.o., while reversing the cognitive dysfunction induced by the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) only at the middle dose of 3 mg/kg. In the ORT, we have found that combined administration of subthreshold doses of SLV330 (1 mg/kg, p.o.) and the AChEI donepezil (0.1 mg/kg, p.o.), that had no discernable effects on performance when given alone, enhanced memory performance in Wistar rats with deficits induced by the muscarinic antagonist scopolamine, suggestive of additive synergistic effects of SLV330 and donepezil on cognitive impairment. Finally, SLV330 was found to have cognition enhancing properties in a time delay paradigm in the SRT at a LED dose of 3 mg/kg (p.o.). In conclusion, the CB(1)R antagonist SLV330 was found to clearly improve memory in several preclinical models for cognitive impairment.

PMID: 20132903 [PubMed - as supplied by publisher]

Gateway compatible lentiviral transfer vectors for ubiquitin promoter driven expression of fluorescent fusion proteins.

Krupka N, Strappe P, Götz J, Ittner LM

Gateway compatible lentiviral transfer vectors for ubiquitin promoter driven expression of fluorescent fusion proteins.

Plasmid. 2010 Feb 1;

Authors: Krupka N, Strappe P, Götz J, Ittner LM

Lentiviral gene delivery has become widely used. Similarly, the Gateway cloning technology that allows restriction-independent cloning of genes into target vectors is becoming increasingly popular. Here, we have generated two Gateway compatible lentiviral transfer vectors for expression of carboxy-terminal fluorescence tagged fusion proteins, pLVU/GFP and pLVU/RED. We used a restriction enzyme-independent PCR-based approach to introduce the carboxy-terminal fluorescence tags, EmGFP and DsRed, respectively. Both vectors combine the advantages of restriction enzyme/ligation-independent cloning using the Gateway system with a attR1-CmR-ccdB-attR2 recombination cassette, together with expression of fluorescence tagged fusion proteins driven by the robust mammalian ubiquitin C (UbC) promoter. We tested the vectors by expressing different proteins together with the carboxy-terminal fluorescence tags in 293T and SH-SY5Y cells. Both pLVU/GFP and pLVU/RED can be utilized in different experiments, including protein localization studies and live-cell in vivo imaging.

PMID: 20132838 [PubMed - as supplied by publisher]

Neuroprotective effects of emodin in rat cortical neurons against beta-amyloid-induced neurotoxicity.

Liu T, Jin H, Sun QR, Xu JH, Hu HT

Neuroprotective effects of emodin in rat cortical neurons against beta-amyloid-induced neurotoxicity.

Brain Res. 2010 Feb 1;

Authors: Liu T, Jin H, Sun QR, Xu JH, Hu HT

Accumulation of beta-amyloid protein (Abeta) in the brain plays an important role in the pathogenesis of Alzheimer's disease (AD). In this study, the neuroprotective effect of emodin extracted from the traditional Chinese medicinal herb Polygonum cuspidatum Sieb. et Zucc against Abeta(25-35)-induced cell death in cultured cortical neurons was investigated. We found that pre-treatment with emodin prevented the cultured cortical neurons from beta-amyloid-induced toxicity. The preventive effect of emodin was blocked by pretreatment with a phosphatidylinositol-3-kinase (PI3K) pathway inhibitor LY294002 or an estrogen receptor (ER) specific antagonist ICI182780, but not by pretreatment with a extracellular signal-related kinases (ERK) inhibitor U0126. Furthermore, we found that emodin exposure induced the activation of the Akt serine/threonine kinase and increased the level of Bcl-2 expression. Moreover, the application of emodin for 24h was able to induce the activation of Abeta(25-35)-suppressed Akt and decrease the activation of the Jun-N-terminal kinases (JNK), but not of ERK. Interestingly, the up-regulation of Akt and Bcl-2 did not occur in the presence of LY294002 or ICI182780, suggesting that emodin-up-regulated Bcl-2 is mediated via ER and PI3K/Akt pathway. Taken together, our results suggest that emodin is an effective neuroprotective drug and is a viable candidate for treating AD.

PMID: 20132797 [PubMed - as supplied by publisher]

ANALYSIS OF beta-AMYLOID (Abeta) DEPOSITION IN THE TEMPORAL LOBE IN ALZHEIMER'S DISEASE USING FOURIER (SPECTRAL) ANALYSIS.

Armstrong RA, Cairns NJ

ANALYSIS OF beta-AMYLOID (Abeta) DEPOSITION IN THE TEMPORAL LOBE IN ALZHEIMER'S DISEASE USING FOURIER (SPECTRAL) ANALYSIS.

Neuropathol Appl Neurobiol. 2010 Jan 29;

Authors: Armstrong RA, Cairns NJ

Abstract Aim: To determine the spatial pattern of beta-amyloid (Abeta) deposition throughout the temporal lobe in Alzheimer's disease (AD). Methods: Sections of the complete temporal lobe from six cases of sporadic AD were immunolabelled with antibody against Abeta. Fourier (spectral) analysis was used to identify sinusoidal patterns in the fluctuation of Abeta deposition in a direction parallel to the pia mater or alveus. Results: Significant sinusoidal fluctuations in density were evident in 81/99 (82%) analyses. In 64% of analyses, two frequency components were present with density peaks of Abeta deposits repeating every 500-1000microm and at distances greater than 1000microm. In 25% of analyses, three or more frequency components were present. The estimated period or wavelength (number of sample units to complete one full cycle) of the first and second frequency components did not vary significantly between gyri of the temporal lobe, but there was evidence that the fluctuations of the classic deposits had longer periods than the diffuse and primitive deposits. Conclusions: (i) Abeta deposits exhibit complex sinusoidal fluctuations in density in the temporal lobe in AD, (ii) fluctuations in Abeta deposition may reflect the formation of Abeta deposits in relation to the modular and vascular structure of the cortex, and (iii) Fourier analysis may be a useful statistical method for studying the patterns of Abeta deposition both in AD and in transgenic models of disease.

PMID: 20132489 [PubMed - as supplied by publisher]

Microglial C5aR (CD88) expression correlates with amyloid-beta deposition in murine models of Alzheimer's Disease.

Ager RR, Fonseca MI, Chu SH, Sanderson SD, Taylor SM, Woodruff TM, Tenner AJ

Microglial C5aR (CD88) expression correlates with amyloid-beta deposition in murine models of Alzheimer's Disease.

J Neurochem. 2010 Feb 2;

Authors: Ager RR, Fonseca MI, Chu SH, Sanderson SD, Taylor SM, Woodruff TM, Tenner AJ

Alzheimer Disease (AD), a progressive neurodegenerative disease characterized by the accumulation of amyloid-beta protein and neuronal loss, is the leading cause of age-related dementia in the world today. The disease is also associated with neuroinflammation, robust activation of astrocytes and microglia and evidence of activation of the complement system, localized with both fibrillar amyloid-beta (fAbeta) plaques and tangles. The observations are consistent with a complement dependent component of AD progression. We have previously shown that inhibition of the major complement receptor for C5a (CD88) with the C5a receptor antagonist (PMX205) results in a significant reduction in pathology in two mouse models of AD. To further characterize the role of complement in AD related neuroinflammation, we examined the age and disease associated expression of CD88 in brain of transgenic mouse models of AD and the influence of PMX205 on the presence of various complement activation products using flow cytometry, western blot and immunohistochemistry. CD88 was found to be upregulated in microglia, in the immediate vicinity of amyloid plaques. While thioflavine plaque load and glial recruitment is significantly reduced after treatment with PMX205, C1q remains co-localized with fAbeta plaques and C3 is still expressed by the recruited astrocytes. Thus, with PMX205, potentially beneficial activities of these early complement components may remain intact, while detrimental activities resulting from C5a-CD88 interaction are inhibited. This further supports the targeted inhibition of specific complement mediated activities as an approach for AD therapy.

PMID: 20132482 [PubMed - as supplied by publisher]

Insulin inhibits Abeta fibrillogenesis through a decrease in the GM1 ganglioside-rich microdomain of neuronal membranes.

Yamamoto N, Taniura H, Suzuki K

Insulin inhibits Abeta fibrillogenesis through a decrease in the GM1 ganglioside-rich microdomain of neuronal membranes.

J Neurochem. 2010 Jan 28;

Authors: Yamamoto N, Taniura H, Suzuki K

Abstract Type 2 diabetes is a risk factor for late-onset Alzheimer's disease. However, the underlying mechanisms remain unknown. To investigate whether insulin is associated with the assembly of amyloid beta-protein from the cell surface, we treated nerve growth factor (NGF)-treated rat pheochromocytoma 12 (PC12) cells with insulin, which is related to the development of diabetes. Insulin treatment induced a decrease in GM1 ganglioside levels in detergent-resistant membrane microdomains of NGF-treated PC12 cells. The insulin-induced effects on GM1 ganglioside levels were regulated by a phosphatidylinositol 3-kinase inhibitor, but not by an extracellular signal-regulated kinase inhibitor. Pretreatment with a protein synthesis inhibitor did not inhibit the decrease in GM1 ganglioside levels induced by insulin. In addition, insulin failed to induce formation of fibrils from soluble amyloid beta-protein or to accelerate GM1 ganglioside-induced fibril formation. Furthermore, assembly of amyloid beta-protein in cultures of NGF-treated PC12 cells was significantly decreased by insulin. These results suggest that insulin inhibits amyloid beta-protein assembly by decreasing GM1 ganglioside expression in detergent-resistant membrane microdomains of neuronal membranes.

PMID: 20132476 [PubMed - as supplied by publisher]

Noradrenaline activation of neurotrophic pathways protects against neuronal amyloid toxicity.

Counts SE, Mufson EJ

Noradrenaline activation of neurotrophic pathways protects against neuronal amyloid toxicity.

J Neurochem. 2010 Jan 28;

Authors: Counts SE, Mufson EJ

Abstract Degeneration of locus coeruleus (LC) noradrenergic forebrain projection neurons is an early feature of Alzheimer's disease (AD). The physiological consequences of this phenomenon are unclear, but observations correlating LC neuron loss with increased AD pathology in LC projection sites suggest that noradrenaline (NA) is neuroprotective. To investigate this hypothesis, we determined that NA protected both hNT human neuronal cultures and rat primary hippocampal neurons from amyloid-beta (Abeta(1-42) and Abeta(25-35)) toxicity. The noradrenergic co-transmitter galanin was also effective at preventing Abeta-induced cell death. NA inhibited Abeta(25-35)-mediated increases in intracellular reactive oxygen species, mitochondrial membrane depolarization, and caspase activation in hNT neurons. NA exerted its neuroprotective effects in these cells by stimulating canonical beta(1) and beta(2) adrenergic receptor signaling pathways involving the activation of cAMP response element binding protein (CREB) and the induction of endogenous nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Treatment with functional blocking antibodies for either NGF or BDNF blocked NA's protective actions against Abeta(1-42) and Abeta(25-35) toxicity in primary hippocampal and hNT neurons, respectively. Taken together, these data suggest that the neuroprotective effects of noradrenergic LC afferents result from stimulating neurotrophic NGF and BDNF autocrine or paracrine loops via beta adrenoceptor activation of the CREB pathway.

PMID: 20132474 [PubMed - as supplied by publisher]

Chronic palliative care: specific practices for Alzheimer's disease sufferers.

Mino JC, Frattini MO

Chronic palliative care: specific practices for Alzheimer's disease sufferers.

J Palliat Care. 2009;25(4):257-63

Authors: Mino JC, Frattini MO

INTRODUCTION: In France, the government's plan to combat Alzheimer's disease takes into consideration mostly the beginnings of the disease; it does not deal with the sufferers' end of life. For this pathology, the very idea of a palliative care phase and its definition are not straightforward. METHOD: The object of this qualitative study was to clarify this idea through a series of interviews with 44 professionals. RESULTS: The study describes three successive phases in the disease trajectory, revealed by changes in the logic of care: the stimulation phase, the chronic palliative care phase, and the terminal palliative phase. CONCLUSION: Alzheimer's disease has a specific phase of chronic palliative care. It presents, for professionals, several types of problems related to communication, pain, and feeding.

PMID: 20131582 [PubMed - in process]

Docosahexaenoic acid (DHA). Monograph.

Docosahexaenoic acid (DHA). Monograph.

Altern Med Rev. 2009 Dec;14(4):391-9

Authors:

PMID: 20030466 [PubMed - indexed for MEDLINE]

Barriers to hospice in patients with Alzheimer.

Lippa CF

Barriers to hospice in patients with Alzheimer.

Am J Alzheimers Dis Other Demen. 2009 Dec-2010 Jan;24(6):443-4

Authors: Lippa CF

PMID: 19938321 [PubMed - indexed for MEDLINE]

Structural and functional characterization of a novel FE65 protein product up-regulated in cognitively impaired FE65 knockout mice.

Cool BH, Zitnik G, Martin GM, Hu Q

Structural and functional characterization of a novel FE65 protein product up-regulated in cognitively impaired FE65 knockout mice.

J Neurochem. 2010 Jan;112(2):410-9

Authors: Cool BH, Zitnik G, Martin GM, Hu Q

FE65 is a multi-modular adaptor protein that binds the cytoplasmic tail of the beta-amyloid precursor protein (APP). Genetic evidence suggests that APP is intimately involved in the pathogenesis of dementias of the Alzheimer type, neurodegenerative disorders that affect multiple cognitive domains, including learning and memory. Evidence from p97FE65-specific knockout mice (lacking the 97 kDa full-length FE65 protein, p97FE65) suggests an important role for FE65 in learning and memory. Interpretation of the learning and memory phenotype, however, is complicated by the up-regulation (compared with wild-type mice) of a novel 60 kDa FE65 isoform (p60FE65). Here, we report an evidence that p60FE65 is translated from an alternative methionine, M261, on the p97FE65 transcript. Thus, p60FE65 has a shortened N-terminus, lacking part of the WW domain that is considered important for nuclear translocation and transactivation of gene expression. Consistently, p60FE65 exhibits an attenuated ability for APP-Gal4-mediated transcription as compared with p97FE65. Similar to p97FE65, however, both transfected and endogenous p60FE65 are able to translocate to the nucleus in cultured cells and in neurons. These results are consistent with earlier evidence from our laboratory that reduced FE65 nuclear signaling may contribute, in part, to the phenotypes observed in p97FE65 knockout mice.

PMID: 19860855 [PubMed - indexed for MEDLINE]