RSSDefects 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.
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]
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.
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]
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]
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.
SuHeXiang Wan essential oil alleviates amyloid beta induced memory impairment through inhibition of tau protein phosphorylation in mice.
Source
Dongguk University Research Institute of Biotechnology, Seoul 100-715, Republic of Korea. jsong0304@dongguk.edu
Abstract
SuHeXiang Wan (SHXW), a traditional Chinese medicine, has been used orally for the treatment of seizures, infantile convulsions and stroke. Previously, we reported the effects of a modified SHXW essential oil in terms of sedative effect, anticonvulsant activity and antioxidative activity. The purpose of this study was to evaluate the potential beneficial effects of SHXW essential oil in neurodegenerative diseases such as Alzheimer's disease (AD). SHXW essential oil was extracted from nine herbs. The mouse AD model was induced by a single injection of amyloid β protein (Aβ(1-42)) into the hippocampus. The animals were divided into four groups, the negative control group injected with Aβ(42-1), the Aβ group injected with Aβ(1-42), the SHXW group inhaled SHXW essential oil and received Aβ(1-42) injection, and the positive control group administered with docosahexaenoic acid (DHA, 10 mg/kg) and with subsequent Aβ(1-42) injection. Mice were analyzed by behavioral tests and immunological examination in the hippocampus. An additional in vitro investigation was performed to examine whether SHXW essential oil inhibits Aβ(1-42) induced neurotoxicity in a human neuroblastoma cell line, SH-SY5Y cells. Pre-inhalation of SHXW essential oil improved the Aβ(1-42) induced memory impairment and suppressed Aβ(1-42) induced JNK, p38 and Tau phosphorylation in the hippocampus. SHXW essential oil suppressed Aβ-induced apoptosis and ROS production via an up-regulation of HO-1 and Nrf2 expression in SH-SY5Y cells. The present study suggests that SHXW essential oil may have potential as a therapeutic inhalation drug for the prevention and treatment of AD.
[The role of CSF markers in the early diagnosis of Alzheimer's disease].
Source
Afdeling Psychiatrie en Neurophyschologie, MUMC, Maastricht. s.vos@maastrichtuniversity.nl
Abstract
BACKGROUND:
Biomarkers in cerebrospinal fluid (CSF) are being used increasingly to diagnose early Alzheimer'sdisease (AD). A CSF profile that is suggestive of ad is an abnormal ratio of the proteins Ab1-42 to total tau.
AIM:
To describe the prevalence and prognosis of a CSF profile in patients without dementia but with subjective memory problems and mild cognitive impairments (MCI) at a memory clinic.
METHOD:
A multi-centre study.
RESULTS:
A European multi-centre study showed that a CSF AD profile was often present in patients with subjective complaints and patients with MCI . The CSF AD profile predicted a decline in cognition and daily functioning over a period of 3 years in patients with MCI. Patients with amnestic MCI and a CSF AD profile developed AD more often within this period than patients without this profile.
CONCLUSION:
CSF markers suggestive of ad are common in persons without dementia. It may be possible to use these markers for the prognosis of patients who have MCI .
Comment in
Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease.
Source
Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA.
Abstract
BACKGROUND:
Apolipoprotein E (APOE) is the most statistically significant genetic risk factor for late-onset Alzheimer disease (LOAD). The linkage disequilibrium pattern around the APOE gene has made it difficult to determine whether all the association signal is derived from APOE or whether there is an independent signal from a nearby gene.
OBJECTIVE:
To attempt to replicate a recently reported association of APOE 3-TOMM40 haplotypes with risk and age at onset.
DESIGN:
We used standard techniques to genotype several polymorphisms in the APOE-TOMM40 region in a large case-control series, in a series with cerebrospinal fluid biomarker data, and in brain tissue.
SETTING:
Alzheimer's Disease Research Center.
PARTICIPANTS:
Research volunteers who were cognitively normal or had Alzheimer disease.
MAIN OUTCOME MEASURES:
Disease status and age at onset.
RESULTS:
We did not replicate the previously reported association of the polyT polymorphism (rs10524523) with risk and age at onset. We found a significant association between rs10524523 and risk of LOAD in APOE 33 homozygotes but in the opposite direction as the previously reported association (the very long allele was underrepresented in cases vs controls in this study (P = .004]). We found no association between rs10524523 and cerebrospinal fluid tau or β-amyloid 42 levels or TOMM40 or APOE gene expression.
CONCLUSIONS:
Although we did not replicate the earlier association between the APOE 3-TOMM40 haplotypes and age at onset, we observed that the polyT polymorphism is associated with risk of LOAD in APOE 33 homozygotes in a large case-control series but in the opposite direction as in the previous study.
- PMID:
- 21825236
- [PubMed - indexed for MEDLINE]
- PMCID: PMC3204798
- [Available on 2012/8/1]
Application of immunosignatures to the assessment of Alzheimer's disease.
Source
Center for Innovations in Medicine, Biodesign Institute, Arizona State University, Tempe, AZ 85287-5901, USA.
Abstract
OBJECTIVE:
Accurate assessment of Alzheimer's disease (AD), both presymptomatically and at different diseasestages, will become increasingly important with the expanding elderly population. There are a number of indications that the immune system is engaged in AD. Here we explore the ability of an antibody-profiling technology to characterize AD and screen for peptides that may be used for a simple diagnostic test.
METHODS:
We developed an array-based system to profile the antibody repertoire of transgenic mice with cerebral amyloidosis (TG) and elderly individuals with or without AD. The array consists of 10,000 random sequence peptides (20-mers) capable of detecting antibody binding patterns, allowing the identification of peptides that mimic epitopes targeted by a donor's serum.
RESULTS:
TG mice exhibited a distinct immunoprofile compared to nontransgenic littermates. Further, we show that dementia patients, including autopsy-confirmed AD subjects, have distinguishable profiles compared to age-matched nondemented people. Using antibodies to different forms of Aβ peptide and blocking protocols, we demonstrate that most of this signature is not due to the subject's antibodies raised against Aβ.
INTERPRETATION:
We propose that "immunosignaturing" technology may have potential as a diagnostic tool in AD.
Copyright © 2011 American Neurological Association.
Visinin-like protein-1: diagnostic and prognostic biomarker in Alzheimer disease.
Source
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Abstract
OBJECTIVE:
There is a growing need to identify cerebrospinal fluid (CSF) markers that can detect Alzheimer's disease(AD) pathology in cognitively normal individuals because it is in this population that disease-modifying therapies may have the greatest chance of success. While AD pathology is estimated to begin ~10-15 years prior to the onset of cognitive decline, substantial neuronal loss is present by the time the earliest signs of cognitive impairment appear. Visinin-like protein-1 (VILIP-1) has demonstrated potential utility as a marker of neuronal injury. Here we investigate CSF VILIP-1 and VILIP-1/amyloid-β42 (Aβ42) ratio as diagnostic and prognostic markers in early AD.
METHODS:
We assessed CSF levels of VILIP-1, tau, phosphorylated-tau181 (p-tau181), and Aβ42 in cognitively normal controls (CNC) (n = 211), individuals with early symptomatic AD (n = 98), and individuals with other dementias (n = 19). Structural magnetic resonance imaging (n = 192) and amyloid imaging with Pittsburgh Compound-B (n = 156) were obtained in subsets of this cohort. Among the CNC cohort, 164 individuals had follow-up annual cognitive assessments for 2-3 years.
RESULTS:
CSF VILIP-1 levels differentiated individuals with AD from CNC and individuals with other dementias. CSF VILIP-1 levels correlated with CSF tau, p-tau181, and brain volumes in AD. VILIP-1 and VILIP-1/Aβ42 predicted future cognitive impairment in CNC over the follow-up period. Importantly, CSF VILIP-1/Aβ42 predicted future cognitive impairment at least as well as tau/Aβ42 and p-tau181/Aβ42.
INTERPRETATION:
These findings suggest that CSF VILIP-1 and VILIP-1/Aβ42 offer diagnostic utility for early AD, and can predict future cognitive impairment in cognitively normal individuals similarly to tau and tau/Aβ42, respectively.
Copyright © 2011 American Neurological Association.
- PMID:
- 21823155
- [PubMed - indexed for MEDLINE]
- PMCID: PMC3154071
- [Available on 2012/8/1]
Reversibility of Tau-related cognitive defects in a regulatable FTD mouse model.
Source
Max Planck Unit for Structural Molecular Biology, c/o DESY, 22607, Hamburg, Germany.
Abstract
The accumulation of proteins such as Tau is a hallmark of several neurodegenerative diseases, e.g., frontotemporal dementia (FTD). So far, many mouse models of tauopathies have been generated by the use of mutated or truncated human Tau isoforms in order to enhance the amyloidogenic character of Tau and to mimic pathological processes similar to those in FTD patients. Our inducible mice express the repeat domain of human Tau (Tau(RD)) carrying the FTDP-17 mutation ΔK280 in a "pro-aggregant" and an "anti-aggregant" version. Based on the enhanced tendency of Tauto aggregate, only the "pro-aggregant" Tau(RD) mice develop Tau pathology (hyperphosphorylation, coassembly of human and mouse Tau, synaptic loss, and neuronal degeneration). We have now carried out behavioral and electrophysiological analyses showing that only the pro-aggregant Tau(RD) mice have impaired learning/memory and a distinct loss of LTP. Remarkably, after suppressing the pro-aggregant human Tau(RD), memory and LTP recover, while neuronal loss persists. Aggregates persist as well but change their composition from mixed human/mouse to mouseTau only. The rescue of cognition and synaptic plasticity is explained by a partial recovery of spine synapses in the hippocampus. These results indicate a tight relationship between the amyloidogenic character of Tau and brain malfunction, and suggest that the cognitive impairment is caused by toxic human Tau(RD) species rather than by mouse Tau aggregates.
Proposal for Alzheimer's diagnosis using molecular buffer and bus network.
Source
Hybrid Computing Research Laboratory, King Mongkut's Institute of Technology Ladkrabang, Bangkok, Thailand.
Abstract
A novel design of an optical trapping tool for tangle protein (tau tangles, β-amyloid plaques) and molecular motor storage and delivery using a PANDA ring resonator is proposed. The optical vortices can be generated and controlled to form the trapping tools in the same way as the optical tweezers. In theory, the trapping force is formed by the combination between the gradient field and scattering photons, and is reviewed. By using the intense optical vortices generated within the PANDA ring resonator, the required molecular volumes can be trapped and moved dynamically within the molecular buffer and bus network. The tangle protein and molecular motor can transport and connect to the required destinations, enabling availability for Alzheimer's diagnosis.
Suppression of a neocortical potassium channel activity by intracellular amyloid-β and its rescue with Homer1a.
Source
Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan.
Abstract
It is proposed that intracellular amyloid-β (Aβ), before extracellular plaque formation, triggers cognitive deficits inAlzheimer disease (AD). Here we report how intracellular Aβ affects neuronal properties. This was done by injecting Aβ protein into rat and mouse neocortical pyramidal cells through whole-cell patch pipettes and by using 3xTg AD model mice, in which intracellular Aβ is accumulated innately. In rats, intracellular application of a mixed Aβ(1-42) preparation containing both oligomers and monomers, but not a monomeric preparation of Aβ(1-40), broadened spike width and augmented Ca(2+) influx via voltage-dependent Ca(2+) channels in neocortical neurons. Both effects were mimicked and occluded by charybdotoxin, a blocker of large-conductance Ca(2+)-activated K(+) (BK) channels, and blocked by isopimaric acid, a BK channel opener. Surprisingly, augmented Ca(2+) influx was caused by elongated spike duration, but not attributable to direct Ca(2+) channel modulation by Aβ(1-42). The Aβ(1-42)-induced spike broadening was blocked by electroconvulsive shock (ECS), which we previously showed to facilitate BK channel opening via expression of the scaffold protein Homer1a. In young 3xTg and wild mice, we confirmed spike broadening by Aβ(1-42), which was again mimicked and occluded by charybdotoxin and blocked by ECS. In Homer1a knock-out mice, ECS failed to block the Aβ(1-42) effect. Single-channel recording on BK channels supported these results. These findings suggest that the suppression of BK channels by intracellular Aβ(1-42) is a possible key mechanism for early dysfunction in the AD brain, which may be counteracted by activity-dependent expression of Homer1a.
Mechanism of inhibition of PP2A activity and abnormal hyperphosphorylation of tau by I2(PP2A)/SET.
Source
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Abstract
Protein phosphatase-2A (PP2A) activity, which is compromised in Alzheimer disease brain, is regulated by two endogenous inhibitors, one of them being I(2)(PP2A), a 277 amino acid long protein also known as SET. Here we report that both the amino terminal fragment (I(2NTF); aa 1-175) and the carboxy terminal fragment (I(2CTF); aa 176-277) of I(2)(PP2A) inhibit PP2A by binding to its catalytic subunit PP2Ac and cause hyperphosphorylation of tau. The C-terminal acidic region in I(2CTF) and Val 92 in I(2NTF) are essential for their association with PP2Ac and inhibition of the phosphatase activity.
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