Friday, January 6, 2012

tau protein function| What is tau protein function|Papers on tau protein function|Research on tau protein function | Publications on tau protein f

Pharmacol Ther. 2011 Dec 22. [Epub ahead of print]

Transglutaminase 2: Biology, Relevance to Neurodegenerative Diseases and Therapeutic Implications.

Abstract

Neurodegenerative disorders are characterized by progressive neuronal loss and the aggregation of disease-specific pathogenic proteins in hallmark neuropathologic lesions. Many of these proteins, including amyloid Αβ, tau, α-synuclein and huntingtin, are cross-linked by the enzymatic activity of transglutaminase 2 (TG2). Additionally, the expression and activity of TG2 is increased in affected brain regions in these disorders. These observations along with experimental evidence in cellular and mouse models suggest that TG2 can contribute to the abnormal aggregation of disease causingproteins and consequently to neuronal damage. This accumulating evidence has provided the impetus to develop inhibitors of TG2 as possible neuroprotective agents. However, TG2 has other enzymatic activities in addition to its cross-linking function and can modulate multiple cellular processes including apoptosis, autophagy, energy production, synaptic function, signal transduction and transcription regulation. These diverse properties must be taken into consideration in designing TG2 inhibitors. In this review, we discuss the biochemistry of TG2, its various physiologic functions and our current understanding about its role in degenerative diseases of the brain. We also describe the different approaches to designing TG2 inhibitors that could be developed as potential disease-modifying therapies.

Copyright © 2011. Published by Elsevier Inc.

PMID:
22212614
[PubMed - as supplied by publisher]
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2.
Neurodegener Dis. 2011 Dec 23. [Epub ahead of print]

Regulation of Physiologic Actions of LRRK2: Focus on Autophagy.

Source

Department of Pharmacology, Boston University School of Medicine, Boston, Mass., USA.

Abstract

Background: Mutations in LRRK2 are associated with familial and sporadic Parkinson's disease (PD). Subjects with PD caused by LRRK2 mutations show pleiotropic pathology that can involve inclusions containing α-synuclein, tau or neither protein. The mechanisms by which mutations in LRRK2 lead to this pleiotropic pathology remain unknown. Objectives: To investigate mechanisms by which LRRK2 might cause PD. Methods: We used systems biology to investigate the transcriptomes from human brains, human blood cells and Caenorhabditis elegans expressing wild-type LRRK2. The role of autophagy was tested in lines of C. elegans expressing LRRK2, V337M tau or both proteins. Neuronal function was measured by quantifying thrashing. Results: Genes regulating autophagy were coordinately regulated with LRRK2. C. elegans expressing V337M tau showed reduced thrashing, as has been noted previously. Coexpressing mutant LRRK2 (R1441C or G2019S) with V337M tau increased the motor deficits. Treating the lines of C. elegans with an mTOR inhibitor that enhances autophagic flux, ridaforolimus, increased the thrashing behavior to the same level as nontransgenic nematodes. Conclusion: These data support a role for LRRK2 in autophagy, raise the possibility that deficits in autophagy contribute to the pathophysiology of LRRK2, and point to a potential therapeutic approach addressing the pathophysiology of LRRK2 in PD.

Copyright © 2011 S. Karger AG, Basel.

PMID:
22204929
[PubMed - as supplied by publisher]
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3.
J Pathol. 2011 Dec 21. doi: 10.1002/path.3977. [Epub ahead of print]

Endoplasmic reticulum stress: a new playER in tauopathies.

Source

Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.

Abstract

The accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER) activates the unfolded protein response (UPR), which involves a set of protein signalling pathways and transcription factors that re-establish homeostasis and normal ER function, adapting cells to ER stress. If this adaptive response is insufficient, the UPR triggers an apoptotic program to eliminate irreversibly damaged cells. Recent observations suggest that ER stress plays an important role in the pathogenesis of various neurodegenerative disorders such as Alzheimer's disease, which is characterized by the deposition of amyloid-beta (Abeta) and hyperphosphorylated tau in susceptible brain regions. Moreover, several studies demonstrate that Abeta induces UPR activation, which in turn promotes tau phosphorylation. In the study by Nijholt and colleagues, reported in the current issue of The Journal of Pathology, the association between UPR activation and tau pathology was investigated in the brain of patients diagnosed with sporadic or familial tauopathies in which Abeta deposits are absent. The authors described that increased levels of UPR activation markers are predominantly observed in neurons within the hippocampus, being correlated with early tau phosphorylation. These findings suggest that UPR activation, which occurs in an Abeta-independent manner, is an early event during taupathology and point to a functional crosstalk between these molecular mechanisms in tauopathies. A better understanding of UPR activation in tauopathies can thus contribute to the design of new therapeutic strategies with the purpose of promoting neuronal cell survival in these disorders. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

PMID:
22190226
[PubMed - as supplied by publisher]
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4.
Phys Rev E Stat Nonlin Soft Matter Phys. 2011 Oct;84(4-1):041903. Epub 2011 Oct 3.

Effect of local thermal fluctuations on folding kinetics: A study from the perspective of nonextensive statistical mechanics.

Source

Departamento de Física e Química, FCFRP, Universidade de São Paulo, 14040-903 Ribeirão Preto, SP, Brazil.

Abstract

The search through the proteins conformational space is thought as an early independent stage of the folding process, governed mainly by the hydrophobic effect. Because of the nanoscopic size of proteins, we assume that the effects of local thermal fluctuations work like folding assistants, managed by the nonextensive parameter q. Using a 27-mer heteropolymer on a cubic lattice, we obtained-by Monte Carlo simulations-kinetic and thermodynamic amounts (such as the characteristic folding time and the native stability) as a function of temperature T and q for a few distinct native targets. We found that for each native structure, at a specific system temperature T, there exists an optimum q^{*} that minimizes the folding characteristic time τ_{min}; for T=1, it is found that q^{*} lies in the interval 1.15±0.05, even for native structures presenting significantly different topological complexities. The distribution of τ_{min} obtained for specific q>1 (nonextensive approach) and temperature T can be fully reproduced for q=1 (Boltzmann approach), but only at higher temperatures T^{'}>T. However, assuming that the complete set of proteins of each organism is optimized to work in a narrow range of temperature, we conclude that-for the present problem-the two approaches, namely, (T,q>1) and (T>T^{'},q=1), cannot be equivalent; it is not a simple matter of reparametrization. Finally, by associating the nonextensive parameter q with the instantaneous degree of compactness of the globule, q becomes a dynamic variable, self-adjusted along the simulation. The results obtained through the q-variable approach are utterly consistent with those obtained by using a target-tuned parameter q^{*}. However, in the former approach, q is automatically adjusted by the chain conformational evolution, eliminating the need to seek for a specific optimized value of q for each case. Besides, using the q-variable approach, different target structures are promptly characterized by inherent distributions of q, which reflect the overall complexity of their corresponding native topologies and energy landscapes.

PMID:
22181171
[PubMed - as supplied by publisher]
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5.
Neurology. 2012 Jan 3;78(1):55-61. Epub 2011 Dec 14.

Cerebrospinal fluid amyloid β and tau in LRRK2 mutation carriers.

Source

Correspondence & reprint requests to Dr. Zhang: zhangj@uw.edu.

Abstract

OBJECTIVE:

The goal of the current investigation was to examine a cohort of symptomatic and asymptomatic LRRK2 mutation carriers, in order to address whether the reported alterations in amyloid β (Aβ) and tau species in the CSF of patients with sporadic Parkinson disease (PD) are a part of PD pathogenesis, the aging process, or a comorbid disease in patients with PD, and to explore the possibility of Aβ and tau as markers of early or presymptomatic PD.

METHODS:

CSF Aβ42, total tau, and phosphorylated tau were measured with Luminex assays in 26 LRRK2 mutation carriers, who were either asymptomatic (n = 18) or had a phenotype resembling sporadic PD (n = 8). All patients also underwent PET scans with (18)F-6-fluoro-l-dopa (FD), (11)C-(±)-α-dihydrotetrabenazine (DTBZ), and (11)C-d-threo-methylphenidate (MP) to measure dopaminergic function in the striatum. The levels of CSF markers were then compared to each PET measurement.

RESULTS:

Reduced CSF Aβ42 and tau levels correlated with lower striatal dopaminergic function as determined by all 3 PET tracers, with a significant association between Aβ42 and FD uptake. When cases were restricted to carriers of the G2019S mutation, the most common LRRK2 variant in our cohort, significant correlations were also observed for tau.

CONCLUSIONS:

The disposition of Aβ and tau is likely important in both LRRK2-related and sporadic PD, even during early phases of the disease. A better understanding of their production, aggregation, and degradation, including changes in their CSF levels, may provide insights into the pathogenesis of PD and the potential utility of these proteins as biomarkers.

PMID:
22170881
[PubMed - in process]
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6.
Rev Esp Geriatr Gerontol. 2011 Oct;46 Suppl 1:39-41.

[Role of biomarkers in the early diagnosis of Alzheimer's disease].

[Article in Spanish]

Source

Unidad de Alzheimer y Otros Trastornos Cognitivos, Servicio de Neurología, ICN, Hospital Clínic de Barcelona, Barcelona, España.

Abstract

Alheimer's disease is the most frequent cause of cognitive decline and behavioral abnormalities in adults. Diagnosis is currently made in the advanced phases. An an early diagnosis in the prodromal phase (or earlier if possible) is required for the prevention of this disease, its early management and the development of potential therapies that could alter its natural course. The syndromic concept of mild cognitive impairment (the presence of detectable and quantifiable deterioration in one of the cognitive domains but without affecting -or without substantially affecting- autonomic performance of instrumental function) and its variants has aided understanding of the predementia stages of Alheimer's disease, even though its etiology may involve multiple factors. The use of biomarkers such as determination of theproteins involved in the disease in cerebrospinal fluid (Aβ42-amyloid, total and phosphorylated tau) and measurement of the hippocampus and entorhinal cortex with magnetic resonance imaging and positron emission tomography (both glucose and amyloid measurements), alone or combined, could allow early and etiologic diagnosis. Patients with Alzheimer's disease show reduced Aβ42-amyloid levels and increased total and phosphorylated tau levels in cerebrospinal fluid.

Copyright © 2011 SEGG. Published by Elsevier Espana. All rights reserved.

PMID:
22152914
[PubMed - in process]
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7.
Exp Neurol. 2011 Nov 16. [Epub ahead of print]

MicroRNA networks surrounding APP and amyloid-β metabolism - Implications for Alzheimer's disease.

Source

Stem Cell and Developmental Biology Division, Victor Chang Cardiac Research Institute (VCCRI), Darlinghurst, NSW 2010, Australia.

Abstract

MicroRNAs (miRNAs) are small non-coding RNA regulators of protein synthesis that function as "fine-tuning" tools of gene expression in development and tissue homeostasis. Their profiles are significantly altered in neurodegenerative diseases such as Alzheimer's disease (AD) that is characterized by both amyloid-β (Aβ) and tau deposition in brain. A key challenge remains in determining how changes in miRNA profiles translate into biological function in a physiological and pathological context. The key lies in identifying specific target genes for deregulated miRNAs and understanding which pathogenic factors trigger their deregulation. Here we review the literature about the intricate network of miRNAs surrounding the regulation of the amyloid precursor protein (APP) from which Aβ is derived by proteolytic cleavage. Normal brain function is highly sensitive to any changes in APP metabolism and miRNAs function at several steps to ensure that the correct APP end product is produced and in the right form and abundance. Disruptions in this miRNA regulatory network may therefore alter Aβ production, which in turn can affect miRNA expression.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
22119426
[PubMed - as supplied by publisher]
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8.
Neuropathology. 2011 Nov 28. doi: 10.1111/j.1440-1789.2011.01274.x. [Epub ahead of print]

Long-term oral intake of aluminium or zinc does not accelerate Alzheimer pathology in AβPP and AβPP/tau transgenic mice.

Source

Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science Department of Human Life Science, Showa Women's University Department of Diagnosis, Prevention and Treatment of Dementia, Graduate School of Juntendo University, Tokyo Department of Pharmacology, International University of Health and Welfare, Tochigi, Japan.

Abstract

Whether or not the oral intake of metals such as aluminium (Al) and zinc (Zn) is a risk for Alzheimer's disease (AD) has been a matter of controversy. Lack of AD pathology in patients with Al encephalopathy indicates Al does not cause AD. On the other hand, some epidemiological studies have suggested high Al increases the occurrence of AD. Our purpose is to test if high Al in drinking water is a risk factor for AD. We administered Al and Zn in drinking water to Tg2576, a transgenic mouse model for amyloid β-protein (Aβ) deposition with the Aβ precursor protein (AβPP) mutations (K670N/M671L), and Tg2576/tau(P301L), a model for Aβ and tau deposition. Deionized water was given to the control Tg2576 and Tg2576/tau. After administration for 4-10 months of approximately 100 mg/kg body weight Al or Zn per day, we were not able to find by quantitative immunohistochemical analyses differences in the deposition of Aβ and taubetween the treated and untreated groups. Nor did the Al or Zn treatment affect the amount of soluble Aβ and Aβ*56, an Aβ oligomer, measured by ELISA or immunoblot. The oral intake of excess Al or Zn does not accelerate AD pathology in the transgenic mouse models for Aβ and tau accumulation. Such results do not seem to support the notion that excessive oral intake of Al or Zn is a risk factor for AD.

© 2011 Japanese Society of Neuropathology.

PMID:
22118300
[PubMed - as supplied by publisher]
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9.
Antioxid Redox Signal. 2011 Nov 27. [Epub ahead of print]

Insights into Mitochondrial Dysfunction: Aging, Amyloid-β and Tau - a deleterious trio.

Source

Universitäre Psychiatrische Kliniken Basel, Neurobiology Lab for Brain Aging & Mental Health, Basel, Switzerland; karen.schmitt@upkbs.ch.

Abstract

Significance. Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder mainly affecting elderly individuals. The pathology of AD is characterized by amyloid plaques (aggregates of amyloid-β (Aβ)) and neurofibrillary tangles (aggregates of tau), but the mechanisms underlying this dysfunction are still partially unclear. Recent Advances. A growing body of evidence supports mitochondrial dysfunction as a prominent and early, chronic oxidative stress-associated event that contributes to synaptic abnormalities and, ultimately, selective neuronal degeneration in AD. Critical issues. In this review, we discuss on the one hand whether mitochondrial decline observed in brain aging is a determinant event in the onset of AD and on the other hand the close inter-relationship of this organelle with Aβ and tauin the pathogenic process underlying AD. Moreover, we summarize evidence from aging and Alzheimer models showing that the harmful trio "aging, Aβ and tau protein" triggers mitochondrial dysfunction through a number of pathways, such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production and interaction with mitochondrial proteins, contributing to the development and progression of the disease. Future Directions. The aging process may weaken the mitochondrial OXPHOS system in a more general way over many years providing a basis for the specific and destructive effects of Aβ and tau. Establishing strategies involving efforts to protect cells at the mitochondrial level by stabilizing or restoring mitochondrial function and energy homeostasis appears to be challenging, but very promising route on the horizon.

PMID:
22117646
[PubMed - as supplied by publisher]
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10.
J Biol Chem. 2011 Nov 18. [Epub ahead of print]

Evidence for the irreversible inhibition of glycogen synthase kinase-3β by tideglusib.

Source

Noscira S.A., Spain.

Abstract

Tideglusib is a GSK-3 inhibitor currently in phase II clinical trials for the treatment of Alzheimer's disease and progressive supranuclear palsy. Sustained oral administration of the compound to a variety of animal models decreasestau hyperphosphorylation, lowers brain amyloid plaque load, improves learning and memory and prevents neuronal loss. We report here that tideglusib inhibits GSK-3β irreversibly, as demonstrated by the lack of recovery in enzyme functionafter the unbound drug has been removed from the reaction medium and the fact that its dissociation rate constant is non-significantly different from zero. Such irreversibility may explain the non-competitive inhibition pattern with respect to ATP shown by tideglusib and perhaps other structurally related compounds. The replacement of Cys-199 by an Ala residue in the enzyme seems to increase the dissociation rate although the drug retains its inhibitory activity with decreased potency and long residence time. In addition, tideglusib failed to inhibit a series of kinases that contain a Cys homologous to Cys-199 in their active site, suggesting that its inhibition of GSK-3β obeys to a specific mechanism and is not a consequence of unspecific reactivity. Results obtained with [35S]-tideglusib do not support unequivocally the existence of a covalent bond between the drug and GSK-3β. The irreversibility of the inhibition and the very low proteinturnover rate observed for the enzyme are particularly relevant from a pharmacological perspective and could have significant implications on its therapeutic potential.

PMID:
22102280
[PubMed - as supplied by publisher]
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11.
J Neurogenet. 2011 Dec;25(4):127-33.

Targeting post-translational modifications on tau as a therapeutic strategy for Alzheimer's disease.

Source

Department of Neurosymptomatics, Merck Research Laboratories, West Point, PA 19486, USA. jacob_marcus@merck.com

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that causes early memory impairment, followed by profound progressive cognitive decline, and eventually death. Neurofibrillary tangles (NFTs) are one of the histopathological hallmarks of AD. NFTs are deposits of insoluble aggregates of the microtubule-binding protein tau, left behind following neuronal loss. Intracellular aggregates of tau, either in soluble or insoluble forms, are thought to disrupt cellular machinery and synaptic function and ultimately lead to neuronal death. As the ultimate pathological endpoint in AD is neuronal loss, there is significant interest in understanding the causes of tau aggregation and deposition in the brain as a potential therapeutic avenue for AD. Post-translational modifications on tau are thought to be an important regulatory mechanism that may contribute to the propensity of tau to aggregate and form NFTs. In addition to phosphorylation, numerous other post-translational modifications have been observed on tau protein. The mechanisms that cause aggregation of tau are unknown, but it is likely that post-translational modifications other than phosphorylation also regulate this process. This review will discuss several post-translational modifications of tau and their roles in modulation of tau function and aggregation in AD.

PMID:
22091726
[PubMed - in process]
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12.
Proteins. 2011 Sep 30. doi: 10.1002/prot.23210. [Epub ahead of print]

Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein.

Source

CNRS-UMR 8576 UGSF-IFR 147, Université des Sciences et Technologies de Lille 1, 59655 Villeneuve d'Ascq Cedex, France.

Abstract

Phosphorylation of the neuronal Tau protein is implicated in both the regulation of its physiological function of microtubule stabilization and its pathological propensity to aggregate into the fibers that characterize Alzheimer's diseased neurons. However, how specific phosphorylation events influence both aspects of Tau biology remains largely unknown. In this study, we address the structural impact of phosphorylation of the Tau protein by Nuclear Magnetic Resonance (NMR) spectroscopy on a functional fragment of Tau (Tau[Ser208-Ser324] = TauF4). TauF4 was phosphorylated by the proline-directed CDK2/CycA3 kinase on Thr231 (generating the AT180 epitope), Ser235, and equally on Thr212 and Thr217 in the Proline-rich region (Tau[Ser208-Gln244] or PRR). These modifications strongly decrease the capacity of TauF4 to polymerize tubulin into microtubules. While all the NMR parameters are consistent with a globally disordered Tau protein fragment, local clusters of structuration can be defined. The most salient result of our NMR analysis is that phosphorylation in the PRR stabilizes a short α-helix that runs from pSer235 till the very beginning of the microtubule-binding region (Tau[Thr245-Ser324] or MTBR of TauF4). Phosphorylation of Thr231/Ser235 creates a N-cap with helix stabilizing role while phosphorylation of Thr212/Thr217 does not induce modification of the local transient secondary structure, showing that the stabilizing effect is sequence specific. Using paramagnetic relaxation experiments, we additionally show a transient interaction between the PRR and the MTBR, observed in both TauF4 and phospho-TauF4. Proteins 2011;. © 2011 Wiley Periodicals, Inc.

Copyright © 2011 Wiley Periodicals, Inc.

PMID:
22072628
[PubMed - as supplied by publisher]
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13.
Biophys J. 2011 Nov 2;101(9):2277-83. Epub 2011 Nov 1.

Analysis of aquaporin-mediated diffusional water permeability by coherent anti-stokes Raman scattering microscopy.

Source

Laboratory for Cell Function Dynamics, Brain Science Institute, The Institute of Physical and Chemical Research (RIKEN), Saitama, Japan.

Abstract

Water can pass through biological membranes via two pathways: simple diffusion through the lipid bilayer, or water-selective facilitated diffusion through aquaporins (AQPs). Although AQPs play an important role in osmotic water permeability (P(f)), the role of AQPs in diffusional water permeability remains unclear because of the difficulty of measuring diffusional water permeability (P(d)). Here, we report an accurate and instantaneous method for measuring the P(d) of a single HeLa S3 cell using coherent anti-Stokes Raman scattering (CARS) microscopy with a quick perfusion device for H(2)O/D(2)O exchange. Ultra-high-speed line-scan CARS images were obtained every 0.488 ms. The average decay time constant of CARS intensities (τ(CARS)) for the external solution H(2)O/D(2)O exchange was 16.1 ms, whereas the intracellular H(2)O/D(2)O exchange was 100.7 ± 19.6 ms. To evaluate the roles of AQP in diffusional water permeability, AQP4 fused with enhanced green fluorescent protein (AQP4-EGFP) was transiently expressed in HeLa S3 cells. The average τ(CARS) for the intracellular H(2)O/D(2)O exchange in the AQP4-EGFP-HeLa S3 cells was 43.1 ± 15.8 ms. We also assessed the cell volume and the cell surface area to calculate P(d). The average P(d) values for the AQP4-EGFP-HeLa S3 cells and the control EGFP-HeLa S3 cells were 2.7 ± 1.0 × 10(-3) and 8.3 ± 2.6 × 10(-4) cm/s, respectively. AQP4-mediated water diffusion was independent of the temperature but was dependent on the expression level of the protein at the plasma membrane. These results suggest the possibility of using CARS imaging to investigate the hydrodynamics of single mammalian cells as well as the regulation of AQPs.

Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.

PMID:
22067168
[PubMed - in process]
PMCID: PMC3207164
[Available on 2012/11/2]
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14.
Arch Gen Psychiatry. 2011 Nov;68(11):1143-50.

Protein binding in patients with late-life depression.

Source

Department of Psychiatry, University of Illinois at Chicago, USA. akumar@psych.uic.edu

Abstract

CONTEXT:

Depression has been identified as a risk factor and a prodrome of dementia. Common neurobiological mechanisms may underlie this clinical and phenomenologic overlap.

OBJECTIVE:

To examine and compare protein (amyloid and tau) binding in critical brain regions in patients diagnosed as having late-life major depressive disorder (MDD) and healthy control individuals using 2-(1-{6-[(2-[(18)F]fluoroethyl)(methyl)-amino]-2-naphthyl}ethylidene) malononitrile ([(18)F]FDDNP) positron emission tomography.

DESIGN:

A cross-section neuroimaging study using positron emission tomography.

SETTING:

University of California, Los Angeles. Patients Our samples comprised 20 patients diagnosed as having MDD and 19 healthy control individuals of comparable age, sex, and educational level. Main Outcome Measure Relative distribution volume in regions of interest was used as the measure of [(18)F]FDDNP binding in all study participants.

RESULTS:

When compared with controls, [(18)F]FDDNP binding was significantly higher overall and in the posterior cingulate and lateral temporal regions in the MDD group.

CONCLUSIONS:

These findings suggest that neuronal injury associated with higher protein load in critical brain regions might provide a mechanism in the pathophysiologic manifestation of MDD in late life and have implications for the therapeutics of depression in elderly individuals.

PMID:
22065530
[PubMed - indexed for MEDLINE]
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15.
Dement Geriatr Cogn Disord. 2011;32(3):193-7. Epub 2011 Nov 3.

Progression from Mild to Pronounced MCI Is Not Associated with Cerebrospinal Fluid Biomarker Deviations.

Source

Institute of Neuroscience and Physiology, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.

Abstract

Background/Aim: Detection of cerebrospinal fluid (CSF) biomarker deviations improve prediction of progression from mild cognitive impairment (MCI) to dementia. However, it is not settled whether the same pattern exists in patients progressing from very mild to more pronounced MCI. Given that neurodegenerative processes occur very early in the disease course, we also expected to find biomarker deviations in these patients. Methods: A total of 246 memory clinic patients with non-progressive (n = 161), progressive (n = 19), or converting (n = 66) MCI, 67 with stable dementia, and 80 controls were followed for 24 months. At baseline, CSF total tau (T-tau), β-amyloid 1-42 (Aβ42) and the light subunit of neurofilament protein (NFL) were determined. Results: Patients with converting MCI and stable dementia had lower CSF Aβ42 concentrations and higher T-tau concentrations and NFL in comparison with controls and non-progressive/progressive MCI (p < 0.0005). No differences were found between progressive and non-progressive MCI. Conclusion: As expected, biomarker deviations predicted progression from MCI to dementia. Contrary to our hypothesis, progression from very mild MCI to more pronounced MCI was not reflected by biomarker deviations. The results suggest that the measured biomarkers are not early disease markers, or alternatively Alzheimer or vascular pathology is not the underlying cause in this patient group.

Copyright © 2011 S. Karger AG, Basel.

PMID:
22057225
[PubMed - in process]
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16.
Neurobiol Aging. 2011 Nov 3. [Epub ahead of print]

GSPE interferes with tau aggregation in vivo: implication for treating tauopathy.

Source

Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA; Alzheimer Disease Research Unit, CIEN Foundation, Queen Sofia Foundation, Madrid, Spain.

Abstract

Tauopathies are characterized by progressive neurodegeneration caused by intracellular accumulation of hyperphosphorylated tau protein aggregates in the brain. The present study was designed to test whether a grape seed polyphenolic extract (GSPE) previously shown to inhibit tau protein aggregation in vitro could benefit tau-mediated neuropathology and behavior deficits in JNPL3 transgenic mice expressing a human tau protein containing the P301L mutation. Nine-month-old JNPL3 mice were treated with GSPE delivered through their drinking water for 6 months. We found that GSPE treatment significantly reduced the number of motor neurons immunoreactive for hyperphosphorylated and conformationally-modified tau in the ventral horns of the spinal cord identified using AT100, PHF-1, AT8, and Alz50tau antibodies. This coincided with a drastically reduced level of hyperphosphorylated and sarcosyl-insoluble tau in spinal cord fractions. Furthermore, the reduction of tau pathology was accompanied by an improvement in the motorfunction assessed by a wire hang test. Collectively, our results suggest that GSPE can interfere with tau-mediated neurodegenerative mechanisms and ameliorate neurodegenerative phenotype in an animal model of tauopathy. Our studies support further evaluation of GSPE for preventing and/or treating of tauopathies in humans.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
22054871
[PubMed - as supplied by publisher]
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17.
Eur J Gynaecol Oncol. 2011;32(5):496-9.

PTEN, tau-AP-3, thymidylate synthase immunohistochemistry scoring expression in patients with uterine leiomyomas, uterine smooth muscle tumors of uncertain malignancy potential and uterine leiomyosarcomas.

Source

Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan.

Abstract

Uterine smooth muscle tumors are frequently classified as benign and malignant. However, an assortment of mitotic counts and nuclear atypia can be indecisive between uncertain malignant potential, and malignant uterine smooth muscle tumors. We applied three immunohistochemical parameters to distinguish between cases of benign, malignant, and those with uncertain malignant histology.

PMID:
22053660
[PubMed - indexed for MEDLINE]
18.
Gene Ther. 2011 Nov 3. doi: 10.1038/gt.2011.166. [Epub ahead of print]

Vector-mediated expression of erythropoietin improves functional outcome after cervical spinal cord contusion injury.

Source

Department of Neurology, University of Michigan and VA Ann Arbor Healthcare System, Ann Arbor, MI, USA.

Abstract

We evaluated the therapeutic effect of erythropoietin (EPO) delivered by direct injection of a nonreplicating herpes simplex virus (HSV)-based vector coding for EPO (vEPO) in a model of cervical hemicord contusion at C7. At 1 h after spinal cord injury (SCI), either vEPO or control vector carrying a reporter gene (vC) was injected into the cord above and below the lesion. Animals injected with vEPO showed a statistically significant improvement in the ipsilateral forelimbfunction, as measured by open-field evaluation of motor performance, forelimb reaching in the cylinder test and misplacement in grid walk. This correlated with preservation of gray matter in the area of the lesion. There was also mild but significant improvement of hindlimb motor function measured by Basso-Beattie-Bresnahan score and computerized gait analysis in vEPO compared with control vector-injected animals. Microtubule-associated protein tau, phosphorylated and nonphosphorylated neurofilament protein and the synaptic proteins synaptophysin and PSD-95 were all significantly increased in the spinal cord of vEPO-treated animals compared with control vector-injected animals. These data suggest that gene transfer of EPO after cervical SCI by minimizing the injury size and enhancing tissue sparing preserves large-caliber axons and promotes synaptogenesis.Gene Therapy advance online publication, 3 November 2011; doi:10.1038/gt.2011.166.

PMID:
22052241
[PubMed - as supplied by publisher]
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19.
J Neurosci. 2011 Nov 2;31(44):15751-6.

Synaptic deficits are rescued in the p25/Cdk5 model of neurodegeneration by the reduction of β-secretase (BACE1).

Source

Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

Abstract

Alzheimer's disease (AD) is the most common cause of dementia, and is characterized by memory loss and cognitive decline, as well as amyloid β (Aβ) accumulation, and progressive neurodegeneration. Cdk5 is a proline-directed serine/threonine kinase whose activation by the p25 protein has been implicated in a number of neurodegenerative disorders. The CK-p25 inducible mouse model exhibits progressive neuronal death, elevated Aβ, reduced synaptic plasticity, and impaired learning following p25 overexpression in forebrain neurons. Levels of Aβ, as well as the APP processing enzyme, β-secretase (BACE1), are also increased in CK-p25 mice. It is unknown what role increased Aβ plays in the cognitive and neurodegenerative phenotype of the CK-p25 mouse. In the current work, we restored Aβ levels in the CK-p25 mouse to those of wild-type mice via the partial genetic deletion of BACE1, allowing us to examine the Aβ-independent phenotype of this mouse model. We show that, in the CK-p25 mouse, normalization of Aβ levels led to a rescue of synaptic and cognitive deficits. Conversely, neuronal loss was not ameliorated. Our findings indicate that increases in p25/Cdk5 activity may mediate cognitive and synaptic impairment via an Aβ-dependent pathway in the CK-p25 mouse. These findings explore the impact of targeting Aβ production in a mouse model of neurodegeneration and cognitive impairment, and how this may translate into therapeutic approaches for sporadic AD.

PMID:
22049418
[PubMed - indexed for MEDLINE]
PMCID: PMC3248793
[Available on 2012/5/2]
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20.
PLoS One. 2011;6(10):e26420. Epub 2011 Oct 14.

Silencing GADD153/CHOP gene expression protects against Alzheimer's disease-like pathology induced by 27-hydroxycholesterol in rabbit hippocampus.

Source

Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, United States of America.

Abstract

Endoplasmic reticulum (ER) stress is suggested to play a key role in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD). Sustained ER stress leads to activation of the growth arrest and leucine zipper transcription factor, DNA damage inducible gene 153 (gadd153; also called CHOP). Activated gadd153 can generate oxidative damage and reactive oxygen species (ROS), increase β-amyloid (Aβ) levels, disturb iron homeostasis and induce inflammation as well as cell death, which are all pathological hallmarks of AD. Epidemiological and laboratory studies suggest that cholesterol dyshomeostasis contributes to the pathogenesis of AD. We have previously shown that the cholesterol oxidized metabolite 27-hydroxycholesterol (27-OHC) triggers AD-like pathology in organotypic slices. However, the extent to which gadd153 mediates 27-OHC effects has not been determined. We silenced gadd153 gene with siRNA and determined the effects of 27-OHC on AD hallmarks in organotypic slices from adult rabbit hippocampus. siRNA to gadd153 reduced 27-OHC-induced Aβ production by mechanisms involving reduction in levels of β-amyloid precursor protein (APP) and β-secretase (BACE1), the enzyme that initiates cleavage of APP to yield Aβ peptides. Additionally, 27-OHC-induced tau phosphorylation, ROS generation, TNF-α activation, and iron and apoptosis-regulatoryprotein levels alteration were also markedly reduced by siRNA to gadd153. These data suggest that ER stress-mediated gadd153 activation plays a central role in the triggering of AD pathological hallmarks that result from incubation of hippocampal slices with 27-OHC. Our results add important insights into cellular mechanisms that underlie the potential contribution of cholesterol metabolism in AD pathology, and suggest that preventing gadd153 activation protects against AD related to cholesterol oxidized products.

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