1.
11C-PiB Imaging of Human Immunodeficiency Virus-Associated Neurocognitive Disorder.
Source
Department of Neurology, Washington University in St. Louis, Campus Box 8111, 660 S Euclid Ave, St Louis, MO 63110. bances@wustl.edu.
Abstract
OBJECTIVE:
To evaluate whether the amyloid-binding agent carbon 11-labeled Pittsburgh Compound B ((11)C-PiB) could differentiate Alzheimer disease (AD) from human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) in middle-aged HIV-positive participants.
DESIGN:
(11)C-PiB scanning, clinical assessment, and cerebrospinal fluid (CSF) analysis were performed. Both χ(2) and t tests assessed differences in clinical and demographic variables between HIV-positive participants and community-living individuals observed at the Knight Alzheimer's Disease Research Center (ADRC). Analysis of variance assessed for regional differences in amyloid-β protein 1-42 (Aβ42) using (11)C-PiB.
SETTING:
An ADRC and HIV clinic.
PARTICIPANTS:
Sixteen HIV-positive participants (11 cognitively normal and 5 with HAND) and 19 ADRC participants (8 cognitively normal and 11 with symptomatic AD).
MAIN OUTCOME MEASURES:
Mean and regional (11)C-PiB binding potentials.
RESULTS:
Participants with symptomatic AD were older (P < .001), had lower CSF Aβ42 levels (P < .001), and had higher CSF tau levels (P < .001) than other groups. Regardless of degree of impairment, HIV-positive participants did not have increased (11)C-PiB levels. Mean and regional binding potentials were elevated for symptomatic AD participants (P < .001).
CONCLUSIONS:
Middle-aged HIV-positive participants, even with HAND, do not exhibit increased (11)C-PiB levels, whereas symptomatic AD individuals have increased fibrillar Aβ42 deposition in cortical and subcortical regions. Observed dissimilarities between HAND and AD may reflect differences in Aβ42 metabolism. (11)C-PiB may provide a diagnostic biomarker for distinguishing symptomatic AD from HAND in middle-aged HIV-positive participants. Future cross-sectional and longitudinal studies are required to assess the utility of (11)C-PiB in older individuals with HAND.
Alzheimer disease biomarkers are associated with body mass index.
Source
Department of Neurology, University of Kansas School of Medicine, Kansas City, KS 66160, USA.
Abstract
OBJECTIVE:
Both low and high body mass index (BMI) has been associated with cognitive impairment and dementia risk, including Alzheimer disease (AD). We examined the relationship of BMI with potential underlying biological substrates for cognitive impairment.
METHODS:
We analyzed cross-sectional data from participants enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with PET imaging using Pittsburgh Compound B (PiB, n = 101) or CSF analyses (n = 405) for β-amyloid peptide (Aβ) and total tau. We assessed the relationship of CSF biomarkers and global PiB uptake with BMI using linear regression controlling for age and sex. We also assessed BMI differences between those who were and were not considered biomarker positive. Finally, we assessed BMI change over 2 years in relationship to AD biomarkers.
RESULTS:
No dementia, mild cognitive impairment (MCI), and AD groups were not different in age, education, or BMI. In the overall sample, CSF Aβ (β = 0.181, p < 0.001), tau (β = -0.179, p < 0.001), tau/Aβ ratio (β = -0.180, p < 0.001), and global PiB uptake (β = -0.272, p = 0.005) were associated with BMI, with markers of increased AD burden associated with lower BMI. Fewer overweight individuals had biomarker levels indicative of pathophysiology (p < 0.01). These relationships were strongest in the MCI and no dementia groups.
CONCLUSIONS:
The presence and burden of in vivo biomarkers of cerebral amyloid and tau are associated with lower BMI in cognitively normal and MCI individuals. This supports previous findings of systemic change in the earliest phases of the disease. Further, MCI in those who are overweight may be more likely to result from heterogeneous pathophysiology.
- PMID:
- 22105948
- [PubMed - indexed for MEDLINE]
- PMCID: PMC3233188
- [Available on 2012/11/22]
Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib.
Source
From Noscira S.A., Avenida de la Industria 52, 28760 Tres Cantos, Spain.
Abstract
Tideglusib is a GSK-3 inhibitor currently in phase II clinical trials for the treatment of Alzheimer disease and progressive supranuclear palsy. Sustained oral administration of the compound to a variety of animal models decreases Tauhyperphosphorylation, 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 function after 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 nonspecific reactivity. Results obtained with [(35)S]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.
Defects in the medial entorhinal cortex and dentate gyrus in the mouse model of Sanfilippo syndrome type B.
Source
Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Abstract
Sanfilippo syndrome type B (MPS IIIB) is characterized by profound mental retardation in childhood, dementia and death in late adolescence; it is caused by deficiency of α-N-acetylglucosaminidase and resulting lysosomal storage of heparan sulfate. A mouse model, generated by homologous recombination of the Naglu gene, was used to study pathological changes in the brain. We found earlier that neurons in the medial entorhinal cortex (MEC) and the dentate gyrus showed a number of secondary defects, including the presence of hyperphosphorylated tau (Ptau) detected with antibodies raised against Ptau in Alzheimer disease brain. By further use of immunohistochemistry, we now show staining in neurons of the same area for beta amyloid, extending the resemblance to Alzheimer disease. Ptau inclusions in the dentate gyrus of MPS IIIB mice were reduced in number when the mice were administered LiCl, a specific inhibitor of Gsk3β. Additional proteins found elevated in MEC include proteins involved in autophagy and the heparan sulfate proteoglycans, glypicans 1 and 5, the latter closely related to the primary defect. The level of secondary accumulations was associated with elevation of glypican, as seen by comparing brains of mice at different ages or with different mucopolysaccharide storage diseases. The MEC of an MPS IIIA mouse had the same intense immunostaining for glypican 1 and other markers as MPS IIIB, while MEC of MPS I and MPS II mice had weak staining, and MEC of an MPS VI mouse had no staining at all for the same proteins. A considerable amount of glypican was found in MEC of MPS IIIB mice outside of lysosomes. We propose that it is the extralysosomal glypican that would be harmful to neurons, because its heparan sulfate branches could potentiate the formation of Ptau and beta amyloid aggregates, which would be toxic as well as difficult to degrade.
SOD1 (Copper/Zinc Superoxide Dismutase) Deficiency Drives Amyloid βProtein Oligomerization and Memory Loss in Mouse Model of Alzheimer Disease.
Source
From Molecular Gerontology.
Abstract
Oxidative stress is closely linked to the pathogenesis of neurodegeneration. Soluble amyloid β (Aβ) oligomers cause cognitive impairment and synaptic dysfunction in Alzheimer disease (AD). However, the relationship between oligomers, oxidative stress, and their localization during disease progression is uncertain. Our previous study demonstrated that mice deficient in cytoplasmic copper/zinc superoxide dismutase (CuZn-SOD, SOD1) have features of drusen formation, a hallmark of age-related macular degeneration (Imamura, Y., Noda, S., Hashizume, K., Shinoda, K., Yamaguchi, M., Uchiyama, S., Shimizu, T., Mizushima, Y., Shirasawa, T., and Tsubota, K. (2006) Proc. Natl. Acad. Sci. U.S.A. 103, 11282-11287). Amyloid assembly has been implicated as a common mechanism of plaque and drusen formation. Here, we show that Sod1 deficiency in an amyloid precursor protein-overexpressing mouse model (AD mouse, Tg2576) accelerated Aβ oligomerization and memory impairment as compared with control AD mouse and that these phenomena were basically mediated by oxidative damage. The increased plaque and neuronal inflammation were accompanied by the generation of N(ε)-carboxymethyl lysine in advanced glycation end products, a rapid marker of oxidative damage, induced by Sod1 gene-dependent reduction. The Sod1 deletion also caused Tau phosphorylation and the lower levels of synaptophysin. Furthermore, the levels of SOD1 were significantly decreased in human AD patients rather than non-AD age-matched individuals, but mitochondrial SOD (Mn-SOD, SOD2) and extracellular SOD (CuZn-SOD, SOD3) were not. These findings suggest that cytoplasmic superoxide radical plays a critical role in the pathogenesis of AD. Activation of Sod1 may be a therapeutic strategy for the inhibition of AD progression.
Challenges associated with curcumin therapy in Alzheimer disease.
Source
INRS-Institut Armand-Frappier, Laval, Québec, Canada.
Abstract
Curcumin, the phytochemical agent in the spice turmeric, which gives Indian curry its yellow colour, is also a traditional Indian medicine. It has been used for millennia as a wound-healing agent and for treating a variety of ailments. The antioxidant, anti-inflammatory, antiproliferative and other properties of curcumin have only recently gained the attention of modern pharmacology. The mechanism of action of curcumin is complex and multifaceted. In part, curcumin acts by activating various cytoprotective proteins that are components of the phase II response. Over the past decade, research with curcumin has increased significantly. In vitro and in vivo studies have demonstrated that curcumin could target pathways involved in the pathophysiology of Alzheimer disease (AD), such as the β-amyloid cascade, tauphosphorylation, neuroinflammation or oxidative stress. These findings suggest that curcumin might be a promising compound for the development of AD therapy. However, its insolubility in water and poor bioavailability have limited clinical trials and its therapeutic applications. To be effective as a drug therapy, curcumin must be combined with other drugs, or new delivery strategies need to be developed.
Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders.
Source
Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. mathias.jucker@uni-tuebingen.de
Abstract
The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism-corruptive protein templating. Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prionlike induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α-synuclein, huntingtin, superoxide dismutase-1, and TDP-43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson/Lewy bodydisease, Huntington disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism-based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations. However, the theory that many chronic neurodegenerative diseases can originate and progress via the seeded corruption of misfolded proteins has the potential to unify experimental and translational approaches to these increasingly prevalent disorders.
Copyright © 2011 American Neurological Association.
- PMID:
- 22028219
- [PubMed - indexed for MEDLINE]
- PMCID: PMC3203752
- [Available on 2012/9/1]
Truncation of tau at E391 promotes early pathologic changes in transgenic mice.
Source
Mental Illness Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA. pammcm@u.washington.edu
Abstract
Proteolytic cleavage of tau at glutamic acid 391 (E391) is linked to the pathogenesis of Alzheimer disease (AD). This C-terminal-truncated tau species exists in neurofibrillary tangles and abnormal neurites in the brains of AD patients and may potentiate tau polymerization. We generated a mouse model that expresses human tau truncated at E391 to begin to elucidate the role of this C-terminal-truncated tau species in the development of tau pathology. Our results show that truncated but otherwise wild-type human tau is sufficient to drive pretangle pathologic changes in tau, including accumulation of insoluble tau, somatodendritic redistribution, formation of pathologic conformations, and dual phosphorylation of tau at sites associated with AD pathology. In addition, these mice exhibit atypical neuritic tauimmunoreactivity, including abnormal neuritic processes and dystrophic neurites. These results suggest that changes intau proteolysis can initiate tauopathy.
- PMID:
- 22002427
- [PubMed - indexed for MEDLINE]
- PMCID: PMC3237612
- [Available on 2012/11/1]
Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years.
Source
Clinical Neuroanatomy, Department of Neurology, and Laboratory for Neuropathology - Institute of Pathology, Center for Clinical Research, University of Ulm, Germany. heiko.braak@uni-ulm.de
Abstract
Two thousand three hundred and thirty two nonselected brains from 1- to 100-year-old individuals were examined using immunocytochemistry (AT8) and Gallyas silver staining for abnormal tau; immunocytochemistry (4G8) and Campbell-Switzer staining were used for the detection ofβ-amyloid. A total of 342 cases was negative in the Gallyas stain but when restaged for AT8 only 10 were immunonegative. Fifty-eight cases had subcortical tau predominantly in the locus coeruleus, but there was no abnormal cortical tau (subcortical Stages a-c). Cortical involvement (abnormal tau in neurites) was identified first in the transentorhinal region (Stage 1a, 38 cases). Transentorhinal pyramidal cells displayed pretangle material (Stage 1b, 236 cases). Pretangles gradually became argyrophilic neurofibrillary tangles (NFTs) that progressed in parallel with NFT Stages I to VI. Pretangles restricted to subcortical sites were seen chiefly at younger ages. Of the total cases, 1,031 (44.2%) had β-amyloid plaques. The first plaques occurred in the neocortex after the onset of tauopathy in the brainstem. Plaques generally developed in the 40s in 4% of all cases, culminating in their tenth decade (75%). β-amyloid plaques and NFTs were significantly correlated (p < 0.0001). These data suggest that tauopathy associated with sporadic Alzheimer disease may begin earlier than previously thought and possibly in the lower brainstem rather than in the transentorhinal region.
Predicting MCI outcome with clinically available MRI and CSF biomarkers.
Source
Department of Radiology, University of California, San Diego, La Jolla, CA 92093-0841, USA.
Abstract
OBJECTIVE:
To determine the ability of clinically available volumetric MRI (vMRI) and CSF biomarkers, alone or in combination with a quantitative learning measure, to predict conversion to Alzheimer disease (AD) in patients with mild cognitive impairment (MCI).
METHODS:
We stratified 192 MCI participants into positive and negative risk groups on the basis of 1) degree of learning impairment on the Rey Auditory Verbal Learning Test; 2) medial temporal atrophy, quantified from Food and Drug Administration-approved software for automated vMRI analysis; and 3) CSF biomarker levels(.) We also stratified participants based on combinations of risk factors. We computed Cox proportional hazards models, controlling for age, to assess 3-year risk of converting to AD as a function of risk group and used Kaplan-Meier analyses to determine median survival times.
RESULTS:
When risk factors were examined separately, individuals testing positive showed significantly higher risk of converting to AD than individuals testing negative (hazard ratios [HR] 1.8-4.1). The joint presence of any 2 risk factors substantially increased risk, with the combination of greater learning impairment and increased atrophy associated with highest risk (HR 29.0): 85% of patients with both risk factors converted to AD within 3 years, vs 5% of those with neither. The presence of medial temporal atrophy was associated with shortest median dementia-free survival (15 months).
CONCLUSIONS:
Incorporating quantitative assessment of learning ability along with vMRI or CSF biomarkers in the clinical workup of MCI can provide critical information on risk of imminent conversion to AD.
- PMID:
- 21998317
- [PubMed - indexed for MEDLINE]
- PMCID: PMC3198979
- [Available on 2012/10/25]
Role of family history for Alzheimer biomarker abnormalities in the adult children study.
Source
Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, Missouri, USA. chengjie@wubios.wustl.edu
Abstract
OBJECTIVE:
To assess whether family history (FH) of Alzheimer disease (AD) alone influences AD biomarker abnormalities.
DESIGN:
Adult Children Study.
SETTING:
Washington University's Charles F. and Joanne Knight Alzheimer's Disease Research Center.
PARTICIPANTS:
A total of 269 cognitively normal middle- to older-aged individuals with and without an FH for AD.
MAIN OUTCOME MEASURES:
Clinical and cognitive measures, magnetic resonance imaging-based brain volumes, diffusion tensor imaging-based white matter microstructure, cerebrospinal fluid biomarkers, and molecular imaging of cerebral fibrillar amyloid with positron emission tomography using the [(11)C] benzothiazole tracer, Pittsburgh compound B.
RESULTS:
A positive FH for AD was associated with an age-related decrease of cerebrospinal fluid Aβ42; the ε4 allele of apolipoprotein E (APOE4) did not alter this effect. Age-adjusted cerebrospinal fluid Aβ42 was decreased for individuals with APOE4 compared with the level for those without, and the decrease was larger for individuals with a positive FH compared with the decrease for those without. The variation of cerebrospinal fluid tau and Pittsburgh compound B mean cortical binding potential increased by age. For individuals younger than 55, an age-related increase in mean cortical binding potential was associated with APOE4 but not FH. For individuals older than 55, a positive FH and a positive APOE4 implied the fastest age-related increase in mean cortical binding potential. A positive FH was associated with decreased fractional anisotropy from diffusion tensor imaging in the genu and splenium of the corpus callosum.
CONCLUSION:
Independent of APOE4, FH is associated with age-related change of several cerebrospinal fluid, Pittsburgh compound B, and diffusion tensor imaging biomarkers in cognitively normal middle- to older-aged individuals, suggesting that non- APOE susceptibility genes for AD influence AD biomarkers.
Current and emerging drug treatment options for Alzheimer's disease: a systematic review.
Source
Neuropsychopharmacology Research Program, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
Abstract
Alzheimer's disease (AD) is a progressive and ultimately fatal condition that causes debilitating memory loss and extensive deterioration of cognitive and functional abilities. Currently available treatments for AD (donepezil, rivastigmine, galantamine and memantine) are symptomatic and do not decelerate or prevent the progression of the disease. These therapies demonstrate modest, but particularly consistent, benefit for cognition, global status and functional ability. The search for disease-modifying interventions has focused largely on compounds targeting the amyloid-β pathway. To date, the treatments targeting this pathway, such as tramiprosate and semagacestat, have been unsuccessful in demonstrating efficacy in clinical stages of testing. At this point, it is likely that not only amyloid-β aggregation but other possible neuronal mechanisms - such as hyperphosphorylated tau, neuro-inflammation and other processes - play important roles in the pathophysiology of this multifactorial disorder. Development of better disease models and biomarkers is essential for the advancement of knowledge of the disease mechanisms. This systematic review critically examines the efficacy and safety data for currently approved drugs and emerging treatments in AD, as well as discussing the present and future directions of innovation in this field.
Decreases in valosin-containing protein result in increased levels of tauphosphorylated at Ser262/356.
Source
Department of Pharmacology and Physiology, University of Rochester, Rochester, NY, USA.
Abstract
VCP/p97 is a multifunctional AAA+-ATPase involved in vesicle fusion, proteasomal degradation, and autophagy. Reported dysfunctions of these processes in Alzheimer disease (AD), along with the linkage of VCP/p97 to inclusion body myopathy with Paget's disease and frontotemporal dementia (IBMPFD) led us to examine the possible linkage of VCP to the AD-relevant protein, tau. VCP levels were reduced in AD brains, but not in the cerebral cortex of an AD mouse model, suggesting that VCP reduction occurs upstream of tau pathology. Genetic reduction of VCP in a primary neuronal model led to increases in the levels of tau phosphorylated at Ser(262/356), indicating that VCP may be involved in regulating post-translational processing of tau in AD, demonstrating a possible functional linkage between tau and VCP.
Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
- PMID:
- 21983102
- [PubMed - indexed for MEDLINE]
- PMCID: PMC3209510
- [Available on 2012/11/4]
Distinct temporal and anatomical distributions of amyloid-β and tauabnormalities following controlled cortical impact in transgenic mice.
Source
Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, United States of America.
Abstract
Traumatic brain injury (TBI) is a major environmental risk factor for Alzheimer's disease. Intracellular accumulations of amyloid-β and tau proteins have been observed within hours following severe TBI in humans. Similar abnormalities have been recapitulated in young 3xTg-AD mice subjected to the controlled cortical impact model (CCI) of TBI and sacrificed at 24 h and 7 days post injury. This study investigated the temporal and anatomical distributions of amyloid-β and tauabnormalities from 1 h to 24 h post injury in the same model. Intra-axonal amyloid-β accumulation in the fimbria was detected as early as 1 hour and increased monotonically over 24 hours following injury. Tau immunoreactivity in the fimbria and amygdala had a biphasic time course with peaks at 1 hour and 24 hours, while tau immunoreactivity in the contralateral CA1 rose in a delayed fashion starting at 12 hours after injury. Furthermore, rapid intra-axonal amyloid-β accumulation was similarly observed post controlled cortical injury in APP/PS1 mice, another transgenic Alzheimer'sdisease mouse model. Acute increases in total and phospho-tau immunoreactivity were also evident in single transgenicTau(P301L) mice subjected to controlled cortical injury. These data provide further evidence for the causal effects of moderately severe contusional TBI on acceleration of acute Alzheimer-related abnormalities and the independent relationship between amyloid-β and tau in this setting.
Fibrillization of human tau is accelerated by exposure to lead via interaction with His-330 and His-362.
Source
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.
Abstract
BACKGROUND:
Neurofibrillary tangles, mainly consisted of bundles of filaments formed by the microtubule-associatedprotein Tau, are a hallmark of Alzheimer disease. Lead is a potent neurotoxin for human being especially for the developing children, and Pb(2+) at high concentrations is found in the brains of patients with Alzheimer disease. However, it has not been reported so far whether Pb(2+) plays a role in the pathology of Alzheimer disease through interaction with human Tau protein and thereby mediates Tau filament formation. In this study, we have investigated the effect of Pb(2+) on fibril formation of recombinant human Tau fragment Tau(244-372) and its mutants at physiological pH.
METHODOLOGY/PRINCIPAL FINDINGS:
As revealed by thioflavin T and 8-anilino-1-naphthalene sulfonic acid fluorescence, the addition of 5-40 µM Pb(2+) significantly accelerates the exposure of hydrophobic region and filament formation of wild-type Tau(244-372) on the investigated time scale. As evidenced by circular dichroism and Fourier transform infrared spectroscopy, fibrils formed by wild-type Tau(244-372) in the presence of 5-40 µM Pb(2+) contain more β-sheet structure than the same amount of fibrils formed by the protein in the absence of Pb(2+). However, unlike wild-type Tau(244-372), the presence of 5-40 µM Pb(2+) has no obvious effects on fibrillization kinetics of single mutants H330A and H362A and double mutant H330A/H362A, and fibrils formed by such mutants in the absence and in the presence of Pb(2+) contain similar amounts of β-sheet structure. The results from isothermal titration calorimetry show that one Pb(2+) binds to one Tau monomer via interaction with His-330 and His-362, with sub-micromolar affinity.
CONCLUSIONS/SIGNIFICANCE:
We demonstrate for the first time that the fibrillization of human Tau protein is accelerated by exposure to lead via interaction with His-330 and His-362. Our results suggest the possible involvement of Pb(2+) in the pathogenesis of Alzheimer disease and provide critical insights into the mechanism of lead toxicity.
Regulation of RCAN1 protein activity by Dyrk1A protein-mediated phosphorylation.
Source
Graduate Program in Neuroscience, Institute for Brain Science and Technology, FIRST Research Group, Inje University, 633-146 Gaegeum-2-Dong, Busanjin-Gu, Busan 614-735, South Korea.
Abstract
Two genes on chromosome 21, namely dual specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) and regulator of calcineurin 1 (RCAN1), have been implicated in some of the phenotypic characteristics of Down syndrome, including the early onset of Alzheimer disease. Although a link between Dyrk1A and RCAN1 and the nuclear factor of activated T cells (NFAT) pathway has been reported, it remains unclear whether Dyrk1A directly interacts with RCAN1. In the present study, Dyrk1A is shown to directly interact with and phosphorylate RCAN1 at Ser(112) and Thr(192) residues. Dyrk1A-mediated phosphorylation of RCAN1 at Ser(112) primes the protein for the GSK3β-mediated phosphorylation of Ser(108). Phosphorylation of RCAN1 at Thr(192) by Dyrk1A enhances the ability of RCAN1 to inhibit the phosphatase activity of calcineurin (Caln), leading to reduced NFAT transcriptional activity and enhanced Tauphosphorylation. These effects are mediated by the enhanced binding of RCAN1 to Caln and its extended half-life caused by Dyrk1A-mediated phosphorylation. Furthermore, an increased expression of phospho-Thr(192)-RCAN1 was observed in the brains of transgenic mice overexpressing the Dyrk1A protein. These results suggest a direct link between Dyrk1A and RCAN1 in the Caln-NFAT signaling and Tau hyperphosphorylation pathways, supporting the notion that the synergistic interaction between the chromosome 21 genes RCAN1 and Dyrk1A is associated with a variety of pathological features associated with DS.
- PMID:
- 21965663
- [PubMed - indexed for MEDLINE]
- PMCID: PMC3220559
- [Available on 2012/11/18]
Alzheimer CSF biomarkers in routine clinical setting.
Source
Clinical Center, Clinique du Colombier, Limoges, France ASTRALAB Clinical Laboratory, Limoges, France.
Abstract
Tabaraud F, Leman JP, Milor AM, Roussie JM, Barrière G, Tartary M, Boutros-Toni F, Rigaud M. Alzheimer CSF biomarkers in routine clinical setting. Acta Neurol Scand: DOI: 10.1111/j.1600-0404.2011.01592.x. © 2011 John Wiley & Sons A/S. Objectives - Our work was aimed to evaluate Alzheimer's disease diagnosis improvement using cerebrospinal fluid biomarkers (CSF) in neurological daily practice. Materials and Methods - For this purpose, 150 patients clinically and neurochemically classified as having AD or cognitive impairment with or without other dementia type were included in the study. The following CSF peptides were studied, blindly to the clinical diagnosis: beta-amyloid(1-42) peptide (Aβ(1-42) ), Tau (T-tau), threonine-181 hyperphosphorylated tau protein (P-tau(181) ), and beta-amyloid(1-40) peptide (Aβ(1-40) ). From these measurements, Innotest® Amyloid Tau Index (IATI) was calculated for each patient. Results - This assessment allowed to separate 83 biochemical profiles of AD and 67 non-Alzheimer'sdisease (non-AD), both AD and non-AD categories match with clinical data amounting to 73% and 90%, respectively. Among mild cognitive impairment (MCI) patients, CSF biomarkers led to discriminate those who are likely to be AD. We devoted a special section to Aβ(1-40) which is not a routine parameter but can help to confirm a pathological amyloid process as Aβ(1-42) /Aβ(1-40) ratio underlining the real decline of the Aβ(1-42) . Conclusions - The interest of biomarkers and their ability to solve awkward cases were carefully noticed all the more when a discrepancy between clinical and CSF biological data was involved. The final proposed algorithm allowed to identify pathogenic forms of AD according to the prevailing role of hyperphosphorylated tau or amyloid beta peptide.
© 2011 John Wiley & Sons A/S.
Cerebrospinal fluid biomarkers, education, brain volume, and future cognition.
Source
Knight Alzheimer’s Disease Research Center, St Louis, MO, USA. cathyr@wustl.edu
Abstract
BACKGROUND:
Cross-sectional studies suggest that the cognitive impact of Alzheimer disease pathology varies depending on education and brain size.
OBJECTIVE:
To evaluate the combination of cerebrospinal fluid biomarkers of β-amyloid(42) (Aβ(42)), tau, and phosphorylated tau (ptau(181)) with education and normalized whole-brain volume (nWBV) to predict incident cognitive impairment.
DESIGN:
Longitudinal cohort study.
SETTING:
Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University, St Louis, Missouri.
PARTICIPANTS:
A convenience sample of 197 individuals 50 years and older with normal cognition (Clinical Dementia Rating of 0) at baseline observed for a mean of 3.3 years.
MAIN OUTCOME MEASURE:
Time to Clinical Dementia Rating ≥ 0.5.
RESULTS:
Three-factor interactions among the baseline biomarker values, education, and nWBV were found for Cox proportional hazards regression models testing tau (P = .02) and ptau (P = .008). In those with lower tau values, nWBV (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.31-0.91; P = .02), but not education, was related to time to cognitive impairment. For participants with higher tau values, education interacted with nWBV to predict incident impairment (P = .01). For individuals with lower ptau values, there was no effect of education or nWBV. Education interacted with nWBV to predict incident cognitive impairment in those with higher ptau values (P = .02).
CONCLUSION:
In individuals with normal cognition and higher levels of cerebrospinal fluid tau and ptau at baseline, time to incident cognitive impairment is moderated by education and brain volume as predicted by the cognitive/brain reserve hypothesis.
- PMID:
- 21911695
- [PubMed - indexed for MEDLINE]
- PMCID: PMC3203689
- [Available on 2012/9/1]
Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial.
Source
Geriatric Research, Education, and Clinical Center, S-182, Veterans Affairs Puget Sound Health Care System, 1660 S Columbian Way, Seattle, WA 98108. scraft@uw.edu.
Abstract
OBJECTIVE:
To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease(AD).
DESIGN:
Randomized, double-blind, placebo-controlled trial.
SETTING:
Clinical research unit of a Veterans Affairs medical center.
PARTICIPANTS:
The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40). Intervention Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington).
MAIN OUTCOME MEASURES:
Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-cog) score and the Alzheimer's Disease Cooperative Study-activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment.
RESULTS:
Outcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayed memory (P < .05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P < .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P < .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions and insulin-minimized progression. No treatment-related severe adverse events occurred.
CONCLUSIONS:
These results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD. Trial Registration clinicaltrials.gov Identifier: NCT00438568.
Structural impact of proline-directed pseudophosphorylation at AT8, AT100, and PHF1 epitopes on 441-residue tau.
Source
Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
Abstract
The intrinsically disordered protein tau becomes excessively phosphorylated and aggregates into neurofibrillary tangles in Alzheimer's disease. To obtain insight into the structural consequences of phosphorylation, we characterized a mutant protein of tau in which epitopes recognized by Alzheimer diagnostic antibodies were mimicked by mutation to glutamic acid [AT8 (S199E, S202E, T205E), AT100 (T212E and S214E), and PHF1 (S396E and S404E)]. A large number of distance restraints obtained from NMR paramagnetic relaxation enhancement in combination with ensemble conformer calculations demonstrate that pseudophosphorylation causes an opening of the transient folding of tau. Together with previous studies on the Parkinson-related protein α-synuclein, our data indicate that networks of transient long-range interactions are common properties of intrinsically disordered proteins and that their modulation is important for aggregation.
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