RSS11C-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.
Developing therapeutic approaches to tau, selected kinases, and related neuronal protein targets.
Source
Center for Neurodegenerative Disease Research, Institute on Aging, Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Abstract
A hallmark of the Alzheimer disease (AD) brain is the presence of inclusions within neurons that are comprised of fibrils formed from the microtubule-stabilizing protein tau. The formation of misfolded multimeric tau species is believed to contribute to the progressive neuron loss and cognitive impairments of AD. Moreover, mutations in tau have been shown to cause a form of frontotemporal lobar degeneration in which tau neuronal inclusions observed in the brain are similar to those seen in AD. Here we review the more compelling strategies that are designed to reduce the contribution of misfolded tau to AD neuropathology, including those directed at correcting a possible loss of tau function resulting from sequestration of cellular tau and to minimizing possible gain-of-function toxicities caused by multimeric tau species. Finally, we discuss the challenges and potential benefits of tau-directed drug discovery programs.
Does Alzheimer's disease exist in all primates? Alzheimer pathology in non-human primates and its pathophysiological implications (I).
Source
Instituto Cajal, CSIC, Madrid, España.
Abstract
INTRODUCTION:
Many publications consider that the Alzheimer's disease (AD) is exclusive to the human species, and that no other animal species suffers from the disease. However, various studies have shown that some species can present with some of the defining characteristics of the disease in humans, both in the neuropathological changes and cognitive-behavioural symptoms.
DEVELOPMENT:
In this work, the results published (PubMed) on the senile brain changes in non-human primates of different degrees of evolution, are reviewed. The neuropathological changes associated with the accumulation of amyloid or highly phosphorylated tau protein are rare outside the primate order, but in all the sub-orders, families, genera and species of non-human primates that have been studied, some senile individuals have shown amyloid accumulation in the brain. Even in some species the presence of these deposits in senility is constant. Changes related to the accumulation of tau protein, are always of very little significance, and have been detected only in some non-human primate species, both little evolved and highly evolved. In different species of non-human primates, some types of cognitive-behavioural changes are present in some senile individuals with greater intensity when compared with both normal adult individuals and other senile individuals of the species. The importance of the determination of the longevity of the species in different habitats (natural habitats, new habitats, semi-liberty, captivity) is stressed in these studies.
CONCLUSIONS:
Morphological and histochemical and cognitive-behavioural features similar to those observed in normal aged man are present in senile non-human primates. Moreover, other characteristics of the non-human primates could be indicative of a pathological «Alzheimer type» ageing.
Copyright © 2011 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.
Interaction between pathogenic proteins in neurodegenerative disorders.
Source
Institute of Clinical Neurobiology, Vienna, Austria.
Abstract
The misfolding and progressive aggregation of specific proteins in selective regions of the nervous system is a seminal occurrence in many neurodegenerative disorders, and the interaction between pathological/toxic proteins to cause neurodegeneration is a hot topic of current neuroscience research. Despite clinical, genetic, and experimental differences, increasing evidence indicates considerable overlap between synucleinopathies, tauopathies and otherprotein-misfolding diseases. Inclusions, often characteristic hallmarks of these disorders, suggest interactions of pathological proteins enganging common downstream pathways. Novel findings that have shifted our understanding in the role of pathologic proteins in the pathogenesis of Alzheimer, Parkinson, Huntington, and prion diseases, have confirmed correlations/overlaps between these and other neurodegenerative disorders. Emerging evidence, in addition to synergistic effects of tau protein, amyloid β, α-synuclein, and other pathologic proteins, suggests that prion-like induction and spreading, involving secreted proteins, are major pathogenic mechanisms in various neurodegenerative diseases, depending on genetic backgrounds and environmental factors. The elucidation of the basic molecular mechanisms underlying the interaction and spreading of pathogenic proteins, suggesting a dualism or triad of neurodegeneration in protein-misfolding disorders, is a major challenge for modern neuroscience, in order to provide a deeper insight into their pathogenesis as a basis of effective diagnosis and treatment. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
Mechanistic involvement of the calpain-calpastatin system in Alzheimerneuropathology.
Source
*Laboratory for Proteolytic Neuroscience, Rikagaku Kenkyūjo (RIKEN) Brain Science Institute, Wako, Saitama, Japan;
Abstract
The mechanism by which amyloid-β peptide (Aβ) accumulation causes neurodegeneration in Alzheimer's disease (AD) remains unresolved. Given that Aβ perturbs calcium homeostasis in neurons, we investigated the possible involvement of calpain, a calcium-activated neutral protease. We first demonstrated close postsynaptic association of calpain activation with Aβ plaque formation in brains from both patients with AD and transgenic (Tg) mice overexpressing amyloid precursor protein (APP). Using a viral vector-based tracer, we then showed that axonal termini were dynamically misdirected to calpain activation-positive Aβ plaques. Consistently, cerebrospinal fluid from patients with AD contained a higher level of calpain-cleaved spectrin than that of controls. Genetic deficiency of calpastatin (CS), a calpain-specific inhibitor protein, augmented Aβ amyloidosis, tau phosphorylation, microgliosis, and somatodendritic dystrophy, and increased mortality in APP-Tg mice. In contrast, brain-specific CS overexpression had the opposite effect. These findings implicate that calpain activation plays a pivotal role in the Aβ-triggered pathological cascade, highlighting a target for pharmacological intervention in the treatment of AD.-Higuchi, M., Iwata, N., Matsuba, Y., Takano, J., Suemoto, T., Maeda, J., Ji, B., Ono, M., Staufenbiel, M., Suhara, T., Saido, T. C. Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology.
BETA-AMYLOID CARRYING THE DUTCH MUTATION HAS DIVERSE EFFECTS ON CALPAIN-MEDIATED TOXICITY IN HIPPOCAMPAL NEURONS.
Source
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Abstract
Hereditary cerebral hemorrhage with amyloidosis-Dutch type is a disorder associated with a missense mutation (E693Q) in the beta-amyloid (Aβ)-coding region of the amyloid precursor protein. This familial disease is characterized by cognitive deficits secondary to intracerebral hemorrhage and, in some cases, progressive Alzheimer disease (AD)-like dementia. Although this mutation was the first ever reported in the human APP gene, little is known about the molecular mechanisms underlying the direct toxic effects of this mutated Aβ on central neurons. In the present study, we assessed the role of calpain-mediated toxicity in such effects using an AD primary culture model system. Our results showed that Dutch mutant Aβ (E22Q) induced calpain-mediated cleavage of dynamin 1 and a significant decrease in synaptic contacts in mature hippocampal cultures. These synaptic deficits were similar to those induced by wild type Aβ. In contrast, calpain-mediated tau cleavage leading to the generation of a 17 kDa neurotoxic fragment, as well as neuronal death, were significantly reduced in E22Q Aβ-treated neurons when compared to WT Aβ-treated ones. This complex regulation of the calpain-mediated toxicity pathway by E22Q Aβ could have some bearings in the pathobiology of this familial AD form.
Cerebrospinal Fluid Proteins Predict Longitudinal Hippocampal Degeneration in Early-stage Dementia of the Alzheimer Type.
Source
*Northwestern University Feinberg School of Medicine, Chicago, IL †Washington University School of Medicine, St. Louis, MO ‡Simon Frasier University, Vancouver, BC, Canada.
Abstract
OBJECTIVE:
Biomarkers are needed to improve the sensitivity and accuracy of diagnosis, and also prognosis, in individuals with early Alzheimer disease (AD). Measures of brain structure and disease-related proteins in the cerebrospinal fluid (CSF) have been proposed as biomarkers, yet relatively little is known about the relationships between such measures. The present study was conducted to assess the relationship between CSF Aβ and tau proteinlevels and longitudinal measures of hippocampal structure in individuals with and without very mild dementia of theAlzheimer type.
DESIGN:
A single CSF sample and longitudinal magnetic resonance scans were collected. The CSF samples were assayed for tau, phosphorylated tau181 (p-tau181), Aβ1-42, and Aβ1-40 using an enzyme-linked immunosorbent assay. Large-deformation diffeomorphic metric mapping was used to generate hippocampal surfaces, and a composite hippocampal surface (previously constructed from 86 healthy participants) was used as a structural reference.
PATIENTS OR OTHER PARTICIPANTS:
Thirteen participants with very mild AD (Clinical Dementia Rating, CDR 0.5) and 11 cognitively normal participants (CDR 0).
INTERVENTION:
None.
MAIN OUTCOME MEASURES:
Initial and rate-of-change measures of total hippocampal volume and displacement of the hippocampal surface within zones overlying the CA1, subiculum, and CA2-4+DG cellular subfields, and their correlations with initial CSF measures.
RESULTS:
Lower CSF Αβ1-42 levels and higher tau/Αβ1-42 and p-tau181/Αβ1-42 ratios were strongly correlated with decreases in hippocampal volume and measures of progressive inward deformations of the CA1 subfield in participants with early AD, but not in cognitively normal participants.
CONCLUSIONS:
Despite the small sample size, we found that Αβ1-42 related and tau-related CSF measures were associated with hippocampal degeneration in individuals with clinically diagnosed early AD and may reflect an association with a common underlying disease mechanism.
[Role of biomarkers in the early diagnosis of Alzheimer's disease].
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'sdisease, 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 withAlzheimer'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.
Publication Types
Publication Types
Evidence for Elevated Cerebrospinal Fluid ERK1/2 Levels in AlzheimerDementia.
Source
Department of Psychiatry and Psychotherapy, Laboratory for Molecular Neurobiology, LVR-Klinikum Essen, University of Duisburg-Essen, Virchowstraße 174, 45147 Essen, Germany.
Abstract
Cerebrospinal fluid (CSF) samples from 33 patients with Alzheimer dementia (AD), 21 patients with mild cognitive impairment who converted to AD during followup (MCI-AD), 25 patients with stable mild cognitive impairment (MCI-stable), and 16 nondemented subjects (ND) were analyzed with a chemiluminescence immunoassay to assess the levels of the mitogen-activated protein kinase ERK1/2 (extracellular signal-regulated kinase 1/2). The results were evaluated in relation to total Tau (tTau), phosphorylated Tau (pTau), and beta-amyloid 42 peptide (Aβ42). CSF-ERK1/2 was significantly increased in the AD group as compared to stable MCI patients and the ND group. Western blot analysis of a pooled cerebrospinal fluid sample revealed that both isoforms, ERK1 and ERK2, and low amounts of doubly phosphorylated ERK2 were detectable. As a predictive diagnostic AD biomarker, CSF-ERK1/2 was inferior to tTau, pTau, and Aβ42.
Interaction between α-synuclein and other proteins in neurodegenerative disorders.
Source
Institute of Clinical Neurobiology, Kenyongasse 18, A-1070 Vienna, Austria. kurt.jellinger@univie.ac.at
Abstract
Protein aggregation is a common characteristic of many neurodegenerative disorders, and the interaction between pathological/toxic proteins to cause neurodegeneration is a hot topic of current neuroscience research. Despite clinical, genetic, and experimental differences, evidence increasingly indicates considerable overlap between synucleinopathies and tauopathies or other protein-misfolding diseases. Inclusions, characteristics of these disorders, also occurring in other neurodegenerative diseases, suggest interactions of pathological proteins engaging common downstream pathways. Novel findings that have shifted our understanding in the role of pathologic proteins in the pathogenesis of Parkinson and Alzheimer diseases have confirmed correlations/overlaps between these and other neurodegenerative disorders. The synergistic effects of α-synuclein, hyperphosphorylated tau, amyloid-β, and other pathologic proteins, and the underlying molecular pathogenic mechanisms, including induction and spread of protein aggregates, are critically reviewed, suggesting a dualism or triad of neurodegeneration in protein-misfolding disorders, although the etiology of most of these processes is still mysterious.
Long-term oral intake of aluminium or zinc does not accelerate Alzheimerpathology 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.
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.
[108th Scientific Meeting of the Japanese Society of Internal Medicine: symposium: 1. Progress in dementia research--dementia disorders andprotein; (4) Tau protein: mechanism and classification of the diseases].
Source
Department of Neurology, Juntendo University and Juntendo Koshigaya Hospital, Japan.
- PMID:
- 22117338
- [PubMed - indexed for MEDLINE]
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]
Publication Types, MeSH Terms, Substances, Grant Support
Publication Types
- Multicenter Study
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, P.H.S.
MeSH Terms
- Aged
- Aged, 80 and over
- Alzheimer Disease/cerebrospinal fluid*
- Alzheimer Disease/pathology
- Alzheimer Disease/radionuclide imaging
- Amyloid beta-Peptides/cerebrospinal fluid*
- Aniline Compounds/diagnostic use
- Biological Markers/cerebrospinal fluid*
- Body Mass Index*
- Cross-Sectional Studies
- Female
- Follow-Up Studies
- Humans
- Magnetic Resonance Imaging/methods
- Male
- Mild Cognitive Impairment/cerebrospinal fluid
- Mild Cognitive Impairment/pathology
- Mild Cognitive Impairment/radionuclide imaging
- Overweight/complications
- Positron-Emission Tomography
- Thiazoles/diagnostic use
- tau Proteins/cerebrospinal fluid*
Substances
- 2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole
- Amyloid beta-Peptides
- Aniline Compounds
- Biological Markers
- Thiazoles
- tau Proteins
Grant Support
- K01AG035042/AG/NIA NIH HHS/United States
- K23NS058252/NS/NINDS NIH HHS/United States
- KL2 RR033177/RR/NCRR NIH HHS/United States
- P30AG035982/AG/NIA NIH HHS/United States
- R01AG033673/AG/NIA NIH HHS/United States
- R01AG034614/AG/NIA NIH HHS/United States
- T32HD057850/HD/NICHD NIH HHS/United States
- U01 AG024904/AG/NIA NIH HHS/United States
- UL1 RR033179/RR/NCRR NIH HHS/United States
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.
Cell Cycle Proteins in Brain in Mild Cognitive Impairment: Insights into Progression to Alzheimer Disease.
Source
Department of Chemistry, Center for Membrane Sciences, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, 40506, USA.
Abstract
Recent studies have demonstrated the re-emergence of cell cycle proteins in brain as patients progress from the early stages of mild cognitive impairment (MCI) into Alzheimer's disease (AD). Oxidative stress markers present in AD have also been shown to be present in MCI brain suggesting that these events occur in early stages of the disease. The levels of key cell cycle proteins, such as CDK2, CDK5, cyclin G1, and BRAC1 have all been found to be elevated in MCI brain compared to age-matched control. Further, peptidyl prolyl cis-trans isomerase (Pin1), a protein that plays an important role in regulating the activity of key proteins, such as CDK5, GSK3-β, and PP2A that are involved in both the phosphorylation state of Tau and in the cell cycle, has been found to be oxidatively modified and downregulated in both AD and MCI brain. Hyperphosphorylation of Tau then results in synapse loss and the characteristic Tau aggregation as neurofibrillary tangles, an AD hallmark. In this review, we summarized the role of cell cycle dysregulation in the progression of disease from MCI to AD. Based on the current literature, it is tempting to speculate that a combination of oxidative stress and cell cycle dysfunction conceivably leads to neurodegeneration.
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.
CSF biomarkers in different phenotypes of Parkinson disease.
Source
, Wein, Austria, kurt.jellinger@univie.ac.at.
Abstract
CSF biomarker studies were performed in 6 patients each with tremor-dominant (TD) and non-tremor-dominant (NT) Parkinson disease (PD) patients, 27 Alzheimer disease (AD) and 17 age-matched controls. In both NT-PD and AD patients total tau levels and the cortex tau/Aβ-42 were significantly increased compared to both TD-PD patients and controls (p < 0.01). These data in a small cohort confirm previous studies, corroborating the opinion that CSF levels oftau protein and the index total-tau/Aβ-42 may be potential markers of the severity of neurodegeneration in PD.
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 thedisease 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.
My daughter (Annabel) suffered schizophrenia for 5 years. I had no idea what was happening and didn’t know where to turn for help. It was hard then because I really didn’t understand the symptoms earlier until she was diagnosed. There was a time she decided to get away from everyone, I was not excluded. I had to sit and cry almost every day because I felt helpless as a single mother (she is all I have got). The anguish I went through taking care of her alone is beyond explanation because there was no support whatsoever from the dad or family members. I fought for proper medical care and humane treatment; I did everything within my reach to get her cured but all to no avail. Countless different medications was prescribed (Zyprexa, fluphenazine, Risperdal, quetiapine, etc.) that she was taking but all we could get was myriad of side effects such as rigidity, drowsiness, dizziness, tremors and restlessness which tends to worsen the already damaged situation. Frustration was the order of the day. I wrote a couple of messages to Ontario Mental Health Foundation for help because watching my daughter go through such was devastating. It was at this foundation someone shared a testimony about DR Sunday herbal medicine, how effective it is and how she went through the most difficult times of her life trying to help her mom fight Schizophrenia. Being that I was already at the verge of giving up because I just couldn't imagine waking up every morning to fight the same demons that left me so tired the night before. I had to contact the doctor,on his email (drsundayherbalcenter@gmail.com) from our conversations; I was relieved and convinced that the result is going to be positive because I was made to contact people with worse cases. Today, the awful situation of my daughter has gone by. Her happy life is back. She is now a schizophrenia survivor and I am glad because my daily routine activities can now kick off without obstructions. Don't let Schizophrenia hinder you from living a desired life and also, never allow anyone to decide for you especially when they don't know what you have to go through to get to where you are. I was almost discouraged by the doctor but then, I remembered that: I have to shield my daughter’s destiny with courage, faith and perseverance because she is not in her right state of mind and that the bravery and freedom from fear is found in the ‘doing’. Her life is now a testimony. After my daughter got cured,from the herbal mix medicine Dr Sunday prepared and sent to me, she said, Mom “I just thought, ‘Well, I’m a weirdo, I’ll never be normal, then I said, my daughter, life itself is a misery and we get stronger in the places we have been broken. Thanks to you Dr. Sunday for your excellent counseling, no more psychotic symptoms for the past 3 years and 4 months now. To know more about Dr.Sunday and the effectiveness of his Herbs and roots extracts and he said he got cures for diseases like Bipolar,DIABETES, HPV,SHINGLES,CANCER, ALS, HEPATITIS B, KIDNEY DISEASE, HERPES, Ovarian Cancer,Pancreatic cancers, Bladder cancer,Skin cancer, Prostate cancer, Glaucoma., Cataracts,Macular degeneration,Cardiovascular disease,Autism,Lung disease.Enlarged prostate,Osteoporosis.Alzheimer's disease,psoriasis ,Tach Diseases,Lupus,Dementia.kidney cancer, lung cancer,. You can reach him on his Email at ... drsundayherbalcenter@gmail.com. I believe you will testify just like me.
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