1.
Regulation of Physiologic Actions of LRRK2: Focus on Autophagy.
Source
Department of Pharmacology, Boston University School of Medicine, Boston, Mass., USA.
Abstract
Background: Mutations in LRRK2 are associated with familial and sporadic Parkinson's disease (PD). Subjects with PD caused by LRRK2 mutations show pleiotropic pathology that can involve inclusions containing α-synuclein, tau or neither protein. The mechanisms by which mutations in LRRK2 lead to this pleiotropic pathology remain unknown. Objectives: To investigate mechanisms by which LRRK2 might cause PD. Methods: We used systems biology to investigate the transcriptomes from human brains, human blood cells and Caenorhabditis elegans expressing wild-type LRRK2. The role of autophagy was tested in lines of C. elegans expressing LRRK2, V337M tau or both proteins. Neuronal function was measured by quantifying thrashing. Results: Genes regulating autophagy were coordinately regulated with LRRK2. C. elegans expressing V337M tau showed reduced thrashing, as has been noted previously. Coexpressing mutant LRRK2 (R1441C or G2019S) with V337M tau increased the motor deficits. Treating the lines of C. elegans with an mTOR inhibitor that enhances autophagic flux, ridaforolimus, increased the thrashing behavior to the same level as nontransgenic nematodes. Conclusion: These data support a role for LRRK2 in autophagy, raise the possibility that deficits in autophagy contribute to the pathophysiology of LRRK2, and point to a potential therapeutic approach addressing the pathophysiology of LRRK2 in PD.
Copyright © 2011 S. Karger AG, Basel.
Therapeutic targets of brain insulin resistance in sporadic Alzheimer's disease.
Source
Departments of Neurology, Neurosurgery, and Neuropathology, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI.
Abstract
Growing evidence supports roles for brain insulin and insulin-like growth factor (IGF) resistance and metabolic dysfunction in the pathogenesis of Alzheimer's disease (AD). Whether the underlying problem stems from a primary disorder of central nervous system (CNS) neurons and glia, or secondary effects of systemic diseases such as obesity, Type 2 diabetes, or metabolic syndrome, the end-results include impaired glucose utilization, mitochondrial dysfunction, increased oxidative stress, neuroinflammation, and the propagation of cascades that result in the accumulation of neurotoxic misfolded, aggregated, and ubiquitinated fibrillar proteins. This article reviews the roles of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism, and discusses therapeutic strategies and lifestyle approaches that could be used to prevent, delay the onset, or reduce the severity of AD. Finally, it is critical to recognize that AD is heterogeneous and has a clinical course that fully develops over a period of several decades. Therefore, early and multi-modal preventive and treatment approaches should be regarded as essential.
- PMID:
- 22201977
- [PubMed - in process]
The tau-like protein in silkworm (Bombyx mori) induces microtubule bundle formation.
Source
The Key Laboratory of Cell Proliferation and Differentiation of Ministry of Education; The State Key Laboratory of Bio-membrane and Membrane Bio-engineering, College of Life Sciences, Peking University, Beijing 100871, China.
Abstract
Tau proteins are major microtubule-associated proteins (MAPs), which promote polymerization of tubulin and determine spacings between microtubules in axons of both the central and peripheral nervous systems (CNS and PNS). Here, we cloned and identified a tau-like protein BmTau from silkworm, Bombyx mori (GenBank accession number FJ904935). The coding sequence of BmTau is 723 bases long and encodes an approximate 30kDa protein. In the C-terminus of BmTau are contained four predicted microtubule-binding domains, which share strong sequence homology to its ortholog in Drosophila melanoganster. Relative real-time PCR analysis showed ubiquitous expression of BmTau in both neurons and non-neural cells, with its mRNA abundantly expressing in brain but significantly less detected in trachea, fat body, and silkgland. Furthermore, immunocytochemical studies in BmN cells transfected with EGFP-BmTau indicated that BmTau functioned as microtubule bundling protein as its orthologues.
- PMID:
- 22201930
- [PubMed - in process]
Metals in alzheimer's disease: a systemic perspective.
Source
Department of Neuroscience, AFaR, Fatebenefratelli Hospital, Rome, Italy, Department of Neurology, Campus Biomedico, University, Rome, Italy.
Abstract
Many results from in vitro and animal studies have highlighted the important role played by specific metals, such as copper, iron and zinc, in the diverse toxic pathways on which Alzheimer's disease (AD) develops. Metals seem to mediate the aggregation and neurotoxicity of amyloid-beta (ABeta), the main constituent of the amyloid plaques, commonly seen in AD (1). The link between metals and AD has been mostly investigated with a focus on their local accumulation in defined areas of the brain critical for AD. In the present review, I have instead approached the issue from the different perspective of a systemic, rather than local, alteration of copper and iron status. This view is supported by the results of a series of in vivo studies demonstrating that abnormalities of metals homeostasis correlate with the main deficits and specific markers of AD, such as ABeta and Tau proteins in the cerebrospinal fluid. These findings clearly suggest that local metals accumulation in brain areas critical for AD should be viewed within a wider framework of metals systemic alteration.
- PMID:
- 22201755
- [PubMed - in process]
Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer's disease.
Source
Departments of Pathology, Neurosurgery, Neurology, and Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
Abstract
Alzheimer's disease (AD) is the most common cause of dementia in North America. Growing evidence supports the concept that AD is fundamentally a metabolic disease that results in progressive impairment in the brain's capacity to utilize glucose and respond to insulin and insulin-like growth factor (IGF) stimulation. Moreover, the heterogeneous nature of AD is only partly explained by the brain's propensity to accumulate aberrantly processed, misfolded and aggregated oligomeric structural proteins, including amyloid-β peptides and hyperphosphorylated tau. Evidence suggests that other factors, including impaired energy metabolism, oxidative stress, neuroinflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into an overarching hypothesis to develop more realistic diagnostic and therapeutic approaches to AD. In this review, the interrelationship between impaired insulin and IGF signalling and amyloid-β pathology is discussed along with potential therapeutic approaches. Impairments in brain insulin/IGF signalling lead to increased expression of amyloid-β precursor protein (AβPP) and accumulation of AβPP-Aβ. In addition, they promote oxidative stress and deficits in energy metabolism, leading to the activation of pro-AβPP-Aβ-mediated neurodegeneration cascades. Although brain insulin/IGF resistance and deficiency can be induced by primary or secondary disease processes, the soaring rates of peripheral insulin resistance associated with obesity, diabetes mellitus and metabolic syndrome quite likely play major roles in the current AD epidemic. Both clinical and experimental data have linked chronic hyperinsulinaemia to cognitive impairment and neurodegeneration with increased AβPP-Aβ accumulation/reduced clearance in the CNS. Correspondingly, both the restoration of insulin responsiveness and the use of insulin therapy can lead to improved cognitive performance, although with variable effects on brain AβPP-Aβ load. On the other hand, experimental evidence supports the concept that the toxic effects of AβPP-Aβ can promote insulin resistance. Together, these findings suggest that a positive feedback loop of progressive neurodegeneration can develop whereby insulin resistance drives AβPP-Aβ accumulation, and AβPP-Aβ fibril toxicity drives brain insulin resistance. This phenomenon could explain why measuring AβPP-Aβ levels in cerebrospinal fluid or imaging of the brain has proven to be inadequate as a stand-alone biomarker for diagnosing AD, and why the clinical trial results of anti-AβPP-Aβ monotherapy have been disappointing. Instead, the aggregate data suggest that brain insulin resistance and deficiency must also be therapeutically targeted to halt AD progression or reverse its natural course. The positive therapeutic effects of different treatments that address the role of brain insulin/IGF resistance and deficiency, including the use of intranasal insulin delivery, incretins and insulin sensitizer agents are discussed along with potential benefits of lifestyle changes to modify risk for developing mild cognitive impairment or AD. Altogether, the data strongly support the notion that we must shift toward the implementation of multimodal rather than unimodal diagnostic and therapeutic strategies for AD.
Endoplasmic reticulum stress: a new playER in tauopathies.
Source
Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
Abstract
The accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER) activates the unfolded protein response (UPR), which involves a set of protein signalling pathways and transcription factors that re-establish homeostasis and normal ER function, adapting cells to ER stress. If this adaptive response is insufficient, the UPR triggers an apoptotic program to eliminate irreversibly damaged cells. Recent observations suggest that ER stress plays an important role in the pathogenesis of various neurodegenerative disorders such as Alzheimer's disease, which is characterized by the deposition of amyloid-beta (Abeta) and hyperphosphorylated tau in susceptible brain regions. Moreover, several studies demonstrate that Abeta induces UPR activation, which in turn promotes tau phosphorylation. In the study by Nijholt and colleagues, reported in the current issue of The Journal of Pathology, the association between UPR activation and tau pathology was investigated in the brain of patients diagnosed with sporadic or familial tauopathies in which Abeta deposits are absent. The authors described that increased levels of UPR activation markers are predominantly observed in neurons within the hippocampus, being correlated with early tau phosphorylation. These findings suggest that UPR activation, which occurs in an Abeta-independent manner, is an early event during taupathology and point to a functional crosstalk between these molecular mechanisms in tauopathies. A better understanding of UPR activation in tauopathies can thus contribute to the design of new therapeutic strategies with the purpose of promoting neuronal cell survival in these disorders. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Effect of chronic administration of estradiol, progesterone, and tibolone on the expression and phosphorylation of glycogen synthase kinase-3β and the microtubule-associated protein tau in the hippocampus and cerebellum of female rat.
Source
Unidad de Investigación Médica en Farmacología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México D.F., México.
Abstract
Gonadal hormones regulate expression and activation of protein tau. Tibolone is a drug used as first- choice comprehensive treatment for the relief of menopausal symptoms, because it and its various metabolites have estrogenic properties and progestogenic/androgenic effects; however, the effect on the activation of tau protein and its signaling cascade in the brain is unknown. We studied the effect of chronic administration of estradiol (E2), progesterone (P4), and tibolone (TIB) on the expression and phosphorylation of microtubule-associated protein tau and glycogen synthase kinase-3β (GSK3β) in the hippocampus and cerebellum of ovariectomized rats. Ovariectomized adult female rats were implanted with pellets of vehicle, E2, or P4 or were treated with TIB by oral administration for 60 days. The animals were sacrificed, and tissue proteins were analyzed by Western blot. We observed that, in the hippocampus, administration of E2, P4, or TIB significantly decreased the protein content of hyperphosphorylated tau and increased the taudephosphorylated form, whereas only treatment with TIB increased the content of the phosphorylated form of GSK3β. In the cerebellum, E2 and TIB treatments resulted in a significant decrease in the expression of hyperphosphorylated tau, whereas E2 and TIB increased phosphorylated GSK3β; P4 had no effect. These results indicate that chronic administration of gonadal hormones and tibolone modulates tau and GSK3β phosphorylation in hippocampus and cerebellum of the rat and may exert a neuroprotective effect in these tissues. © 2011 Wiley Periodicals, Inc.
Copyright © 2011 Wiley Periodicals, Inc.
Effect of local thermal fluctuations on folding kinetics: A study from the perspective of nonextensive statistical mechanics.
Source
Departamento de Física e Química, FCFRP, Universidade de São Paulo, 14040-903 Ribeirão Preto, SP, Brazil.
Abstract
The search through the proteins conformational space is thought as an early independent stage of the folding process, governed mainly by the hydrophobic effect. Because of the nanoscopic size of proteins, we assume that the effects of local thermal fluctuations work like folding assistants, managed by the nonextensive parameter q. Using a 27-mer heteropolymer on a cubic lattice, we obtained-by Monte Carlo simulations-kinetic and thermodynamic amounts (such as the characteristic folding time and the native stability) as a function of temperature T and q for a few distinct native targets. We found that for each native structure, at a specific system temperature T, there exists an optimum q^{*} that minimizes the folding characteristic time τ_{min}; for T=1, it is found that q^{*} lies in the interval 1.15±0.05, even for native structures presenting significantly different topological complexities. The distribution of τ_{min} obtained for specific q>1 (nonextensive approach) and temperature T can be fully reproduced for q=1 (Boltzmann approach), but only at higher temperatures T^{'}>T. However, assuming that the complete set of proteins of each organism is optimized to work in a narrow range of temperature, we conclude that-for the present problem-the two approaches, namely, (T,q>1) and (T>T^{'},q=1), cannot be equivalent; it is not a simple matter of reparametrization. Finally, by associating the nonextensive parameter q with the instantaneous degree of compactness of the globule, q becomes a dynamic variable, self-adjusted along the simulation. The results obtained through the q-variable approach are utterly consistent with those obtained by using a target-tuned parameter q^{*}. However, in the former approach, q is automatically adjusted by the chain conformational evolution, eliminating the need to seek for a specific optimized value of q for each case. Besides, using the q-variable approach, different target structures are promptly characterized by inherent distributions of q, which reflect the overall complexity of their corresponding native topologies and energy landscapes.
Frontotemporal lobar degeneration related proteins induce only subtle memory-related deficits when bilaterally overexpressed in the dorsal hippocampus.
Source
Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA 71130, USA.
Abstract
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease that involves cognitive decline and dementia. To model the hippocampal neurodegeneration and memory-related behavioral impairment that occurs in FTLD and othertau and TDP-43 proteinopathy diseases, we used an adeno-associated virus serotype 9 (AAV9) vector to induce bilateral expression of either microtubule-associated protein tau or transactive response DNA binding protein 43kDa (TDP-43) in adult rat dorsal hippocampus. Human wild-type forms of tau or TDP-43 were expressed. The vectors/doses were designed for moderate expression levels within neurons. Rats were evaluated for acquisition and retention in the Morris water task over 12weeks after gene transfer. Neither vector altered acquisition performance compared to controls. In measurements of retention, there was impairment in the TDP-43 group. Histological examination revealed specific loss of dentate gyrus granule cells and concomitant gliosis proximal to the injection site in the TDP-43 group, with shrinkage of the dorsal hippocampus. Despite specific tau pathology, the tau gene transfer surprisingly did not cause obvious neuronal loss or behavioral impairment. The data demonstrate that TDP-43 produced mild behavioral impairment and hippocampal neurodegeneration in rats, whereas tau did not. The models could be of value for studying mechanisms of FTLD and other diseases with tau and TDP-43 pathology in the hippocampus including Alzheimer's disease, with relevance to early stage mild impairment.
Copyright © 2011. Published by Elsevier Inc.
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 other protein-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.
Cerebrospinal fluid amyloid β and tau in LRRK2 mutation carriers.
Source
Correspondence & reprint requests to Dr. Zhang: zhangj@uw.edu.
Abstract
OBJECTIVE:
The goal of the current investigation was to examine a cohort of symptomatic and asymptomatic LRRK2 mutation carriers, in order to address whether the reported alterations in amyloid β (Aβ) and tau species in the CSF of patients with sporadic Parkinson disease (PD) are a part of PD pathogenesis, the aging process, or a comorbid disease in patients with PD, and to explore the possibility of Aβ and tau as markers of early or presymptomatic PD.
METHODS:
CSF Aβ42, total tau, and phosphorylated tau were measured with Luminex assays in 26 LRRK2 mutation carriers, who were either asymptomatic (n = 18) or had a phenotype resembling sporadic PD (n = 8). All patients also underwent PET scans with (18)F-6-fluoro-l-dopa (FD), (11)C-(±)-α-dihydrotetrabenazine (DTBZ), and (11)C-d-threo-methylphenidate (MP) to measure dopaminergic function in the striatum. The levels of CSF markers were then compared to each PET measurement.
RESULTS:
Reduced CSF Aβ42 and tau levels correlated with lower striatal dopaminergic function as determined by all 3 PET tracers, with a significant association between Aβ42 and FD uptake. When cases were restricted to carriers of the G2019S mutation, the most common LRRK2 variant in our cohort, significant correlations were also observed for tau.
CONCLUSIONS:
The disposition of Aβ and tau is likely important in both LRRK2-related and sporadic PD, even during early phases of the disease. A better understanding of their production, aggregation, and degradation, including changes in their CSF levels, may provide insights into the pathogenesis of PD and the potential utility of these proteins as biomarkers.
A Blood-Based Screening Tool for Alzheimer's Disease That Spans Serum and Plasma: Findings from TARC and ADNI.
Source
Department of Neurology, F. Marie Hall Institute for Rural and Community Health, Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, Texas, United States of America.
Abstract
CONTEXT:
There is no rapid and cost effective tool that can be implemented as a front-line screening tool for Alzheimer's disease (AD) at the population level.
OBJECTIVE:
To generate and cross-validate a blood-based screener for AD that yields acceptable accuracy across both serum and plasma.
DESIGN, SETTING, PARTICIPANTS:
Analysis of serum biomarker proteins were conducted on 197 Alzheimer's disease (AD) participants and 199 control participants from the Texas Alzheimer's Research Consortium (TARC) with further analysis conducted on plasma proteins from 112 AD and 52 control participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The full algorithm was derived from a biomarker risk score, clinical lab (glucose, triglycerides, total cholesterol, homocysteine), and demographic (age, gender, education, APOE*E4 status) data.
MAJOR OUTCOME MEASURES:
Alzheimer's disease.
RESULTS:
11 proteins met our criteria and were utilized for the biomarker risk score. The random forest (RF) biomarker risk score from the TARC serum samples (training set) yielded adequate accuracy in the ADNI plasma sample (training set) (AUC = 0.70, sensitivity (SN) = 0.54 and specificity (SP) = 0.78), which was below that obtained from ADNI cerebral spinal fluid (CSF) analyses (t-tau/Aβ ratio AUC = 0.92). However, the full algorithm yielded excellent accuracy (AUC = 0.88, SN = 0.75, and SP = 0.91). The likelihood ratio of having AD based on a positive test finding (LR+) = 7.03 (SE = 1.17; 95% CI = 4.49-14.47), the likelihood ratio of not having AD based on the algorithm (LR-) = 3.55 (SE = 1.15; 2.22-5.71), and the odds ratio of AD were calculated in the ADNI cohort (OR) = 28.70 (1.55; 95% CI = 11.86-69.47).
CONCLUSIONS:
It is possible to create a blood-based screening algorithm that works across both serum and plasma that provides a comparable screening accuracy to that obtained from CSF analyses.
- PMID:
- 22163278
- [PubMed - as supplied by publisher]
- PMCID: PMC3233542
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 protein levels and longitudinal measures of hippocampal structure in individuals with and without very mild dementia of the Alzheimer 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.
Linking Amyloid-β and Tau: Amyloid-β Induced Synaptic Dysfunction via Local Wreckage of the Neuronal Cytoskeleton.
Source
Max Planck Unit for Structural Molecular Biology, Hamburg, Germany.
Abstract
Background: In Alzheimer's disease (AD), amyloid-β (Aβ) is the major component of extracellular plaques, whereas the microtubule-associated protein tau forms the main component of intracellular tangles. In contrast to frontotemporal dementias and other neurodegenerative diseases, both proteins form pathological aggregates and are considered key players for the development of AD. However, the connection between Aβ and tau and the functional loss of neurons and synapses, which ultimately lead to cognitive impairments, is still not well understood. Objectives: Making use of primary neurons exposed to Aβ oligomers, we sought to determine how tau mediates the Aβ-induced neuronal dysfunction. Additionally, we asked how the microtubule cytoskeleton is involved in the combined Aβ and tau toxicity. Methods: We exposed mature primary rat neurons with developed synapses to Aβ oligomers and used immunofluorescence and electron microscopy to investigate tau, actin, neurofilament and microtuble cytoskeleton changes. Results: Aβ oligomers preferentially associate with synapses, notably dendritic spines, throughout the neuronal cell culture. As a consequence, endogenous tau gets missorted from the axonal into the somatodendritic compartment in a subset of cells. These missorted cells also display missorting of neurofilaments, and a dramatic loss of microtubules, which can be prevented by the microtubule stabilizer taxol. Conclusions: Aβ causes tau missorting, loss of neuronal cell polarity and loss of dendritic microtubules. This in turn leads to impaired organelle/mitochondria transport, whereby synapses cannot be maintained properly and eventually decay. The data support the view that the microtubule cytoskeleton is a valid therapeutic target in AD.
Copyright © 2011 S. Karger AG, Basel.
[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's disease, even though its etiology may involve multiple factors. The use of biomarkers such as determination of theproteins involved in the disease in cerebrospinal fluid (Aβ42-amyloid, total and phosphorylated tau) and measurement of the hippocampus and entorhinal cortex with magnetic resonance imaging and positron emission tomography (both glucose and amyloid measurements), alone or combined, could allow early and etiologic diagnosis. Patients with Alzheimer's disease show reduced Aβ42-amyloid levels and increased total and phosphorylated tau levels in cerebrospinal fluid.
Copyright © 2011 SEGG. Published by Elsevier Espana. All rights reserved.
Rac1b Increases with Progressive Tau Pathology within Cholinergic Nucleus Basalis Neurons in Alzheimer's Disease.
Source
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
Abstract
Cholinergic basal forebrain (CBF) nucleus basalis (NB) neurons display neurofibrillary tangles (NFTs) during Alzheimer's disease (AD) progression, yet the mechanisms underlying this selective vulnerability are currently unclear. Rac1, a member of the Rho family of GTPases, may interact with the proapoptotic pan-neurotrophin receptor p75(NTR) to induce neuronal cytoskeletal abnormalities in AD NB neurons. Herein, we examined the expression of Rac1b, a constitutively active splice variant of Rac1, in NB cholinergic neurons during AD progression. CBF tissues harvested from people who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment, or AD were immunolabeled for both p75(NTR) and Rac1b. Rac1b appeared as cytoplasmic diffuse granules, loosely aggregated filaments, or compact spheres in p75(NTR)-positive NB neurons. Although Rac1b colocalized with tau cytoskeletal markers, the percentage of p75(NTR)-immunoreactive neurons expressing Rac1b was significantly increased only in AD compared with both mild cognitive impairment and NCI. Furthermore, single-cell gene expression profiling with custom-designed microarrays showed down-regulation of caveolin 2, GNB4, and lipase A in AD Rac1b-positive/p75(NTR)-labeled NB neurons compared with Rac1b-negative/p75(NTR)-positive perikarya in NCI. These proteins are involved in Rac1 pathway/cell cycle progression and lipid metabolism. These data suggest that Rac1b expression acts as a modulator or transducer of various signaling pathways that lead to NFT formation and membrane dysfunction in a subgroup of CBF NB neurons in AD.
Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer's disease.
Source
Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland; Department of Neurology, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland.
Abstract
The p62/sequestosome-1 is a multifunctional protein containing several protein-protein interaction domains. Through these interactions p62 is involved in the regulation of cellular signaling and protein trafficking, aggregation and degradation. p62 protein can bind through its UBA motif to ubiquitinated proteins and control their aggregation and degradation via either autophagy or proteasomes. p62 protein has been reported to be seen in association with the intracellular inclusions in primary and secondary tauopathies, α-synucleinopathies and other neurodegenerative brain disorders displaying inclusions with misfolded proteins. In Alzheimer's disease (AD), p62 protein is associated with neurofibrillary tangles composed primarily of hyperphosphorylated tau protein and ubiquitin. Increasing evidence indicates that p62 has an important role in the degradation of tau protein. The lack of p62 protein expression provokes the tau pathology in mice. Recent studies have demonstrated that the p62 gene expression and cytoplasmic p62 protein levels are significantly reduced in the frontal cortex of AD patients. Decline in the level of p62 protein can disturb the signaling pathways of Nrf2, cyclic AMP and NF-κB and in that way increase oxidative stress and impair neuronal survival. We will review here the molecular and functional characteristics of p62 protein and outline its potential role in the regulation of Alzheimer's pathogenesis.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Cells in the female retrotrapezoid region upregulate c-fos in response to 10%, but not 5%, carbon dioxide.
Source
Biology Department, Dickinson College, Carlisle, PA, USA; Neuroscience Program, Dickinson College, Carlisle, PA, USA.
Abstract
The retrotrapezoid nucleus (RTN) is thought to regulate breathing in response to changes in blood carbon dioxide (CO(2)), and to make a vital contribution to respiratory drive, especially during sleep. However, cells in the female RTN fail to upregulate c-fos in response to low level CO(2) exposure, while cells in the male RTN have a robust upregulation of c-fos in response to low level CO(2) exposure. In this study, we examined the possibility that the female RTN has a higher threshold for c-fos upregulation in response to CO(2). Following exposure of Fos-Tau-LacZ (FTL) transgenic mice to 10% CO(2), c-fos was upregulated in just as many cells in the female as in the male RTN. In addition, the male RTN responded equivalently to 5% and 10% CO(2), consistent with a lack of a dose response to CO(2) in the male RTN. Cells in the nearby facial nucleus upregulated c-fos in the same number of cells regardless of sex or gas exposure, confirming that the sex difference in the RTN is unique to that nucleus. We propose that the male and female RTN upregulate c-fos differently in response to CO(2) due to differences in the transcriptional regulation by estrogens of genes that encode proteins related to neuronal excitability or specifically related to central chemoreception, such as potassium channels. These findings could have clinical relevance to sleep related breathing disorders that disproportionately affect males, including the sudden infant death syndrome and sleep apnea.
Copyright © 2011 Elsevier B.V. All rights reserved.
Pitavastatin decreases tau levels via the inactivation of Rho/ROCK.
Source
Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Abstract
Epidemiological studies have shown that long-term treatment with statins decreases the risk of developing Alzheimer's disease. Statins have pleiotropic effects by lowering the concentration of isoprenoid intermediates. Although several studies have shown that statins may reduce amyloid beta protein levels, there have been few reports on the interaction between statins and tau. We report here that pitavastatin reduces total and phosphorylated tau levels in a cellular model of tauopathy, and in primary neuronal cultures. The decrease caused by pitavastatin is reversed by the addition of mevalonate, or geranylgeranyl pyrophosphate. The maturation of small G proteins, including RhoA was disrupted by pitavastatin, as was the activity of glycogen synthase kinase 3β (GSK3β), a major tau kinase. Toxin A, inhibitor of glycosylation of small G proteins, and Rho kinase (ROCK) inhibitor decreased phosphorylated tau levels. Rho kinase inhibitor also inactivated glycogen synthase kinase 3β. Although the mechanisms responsible for the reduction in tauprotein by pitavastatin require further examination, this report sheds light on possible therapeutic approaches to tauopathy.
Copyright © 2011 Elsevier Inc. All rights reserved.
Interaction between α-Synuclein and Other Proteins in Neurodegenerative Disorders.
Source
Institute of Clinical Neurobiology, Kenyongasse 18, A-1070 Vienna, Austria.
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.
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