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Search Results: 1 - 10 of 87301 matches for " Dennis W Dickson "
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Regional patterns of atrophy on MRI in Alzheimer’s disease: Neuropsychological features and progression rates in the ADNI cohort  [PDF]
Ranjan Duara, David A. Loewenstein, Qian Shen, Warren Barker, Maria T. Greig, Daniel Varon, Melissa E. Murray, Dennis W. Dickson
Advances in Alzheimer's Disease (AAD) , 2013, DOI: 10.4236/aad.2013.24019
Abstract: Background: Discrete clinical and pathological subtypes of Alzheimer’s disease (AD) with variable presentations and rates of progression are well known. These subtypes may have specific patterns of regional brain atrophy, which are identifiable on MRI scans. Methods: To examine distinct regions which had distinct underlying patterns of cortical atrophy, factor analytic techniques applied to structural MRI volumetric data from cognitively normal (CN) (n = 202), amnestic mild cognitive impairment (aMCI) (n = 333) or mild AD (n = 146) subjects, in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database was applied. This revealed the existence of two neocortical (NeoC-1 and NeoC-2), and a limbic cluster of atrophic brain regions. The frequency and clinical correlates of these regional patterns of atrophy were evaluated among the three diagnostic groups, and the rates of progression from aMCI to AD, over 24 months were evaluated. Results: Discernable patterns of regional atrophy were observed in about 29% of CN, 55% of aMCI and 83% of AD subjects. Heterogeneity in clinical presentation and APOE ε4 frequency were associated with regional patterns of atrophy on MRI scans. The most rapid progression rates to dementia among aMCI subjects (n = 224), over a 24-month period, were in those with NeoC-1 regional impairment (68.2%), followed by the Limbic regional impairment (48.8%). The same pattern of results was observed when only aMCI amyloid positive subjects were examined. Conclusions: The neuroimaging results closely parallel findings described recently among AD patients with the hippocampal sparing and limbic subtypes of AD neuropathology at autopsy. We conclude that NeoC-1, Limbic and other patterns of MRI atrophy may be useful markers for predicting the rate of progression of aMCI to AD and could have utility selecting individuals at higher risk for progression in clinical trials.
-Amyloid Degradation and Alzheimer's Disease
Deng-Shun Wang,Dennis W. Dickson,James S. Malter
Journal of Biomedicine and Biotechnology , 2006, DOI: 10.1155/jbb/2006/58406
Abstract: Extensive β-amyloid (Aβ) deposits in brain parenchyma in the form of senile plaques and in blood vessels in the form of amyloid angiopathy are pathological hallmarks of Alzheimer's disease (AD). The mechanisms underlying Aβ deposition remain unclear. Major efforts have focused on Aβ production, but there is little to suggest that increased production of Aβ plays a role in Aβ deposition, except for rare familial forms of AD. Thus, other mechanisms must be involved in the accumulation of Aβ in AD. Recent data shows that impaired clearance may play an important role in Aβ accumulation in the pathogenesis of AD. This review focuses on our current knowledge of Aβ-degrading enzymes, including neprilysin (NEP), endothelin-converting enzyme (ECE), insulin-degrading enzyme (IDE), angiotensin-converting enzyme (ACE), and the plasmin/uPA/tPA system as they relate to amyloid deposition in AD.
β -Amyloid Degradation and Alzheimer's Disease
Deng-Shun Wang,Dennis W. Dickson,James S. Malter
Journal of Biomedicine and Biotechnology , 2006,
Abstract: Extensive β -amyloid (A β ) deposits in brain parenchyma in the form of senile plaques and in blood vessels in the form of amyloid angiopathy are pathological hallmarks of Alzheimer's disease (AD). The mechanisms underlying A β deposition remain unclear. Major efforts have focused on A β production, but there is little to suggest that increased production of A β plays a role in A β deposition, except for rare familial forms of AD. Thus, other mechanisms must be involved in the accumulation of A β in AD. Recent data shows that impaired clearance may play an important role in A β accumulation in the pathogenesis of AD. This review focuses on our current knowledge of A β -degrading enzymes, including neprilysin (NEP), endothelin-converting enzyme (ECE), insulin-degrading enzyme (IDE), angiotensin-converting enzyme (ACE), and the plasmin/uPA/tPA system as they relate to amyloid deposition in AD.
Three Repeat Isoforms of Tau Inhibit Assembly of Four Repeat Tau Filaments
Stephanie J. Adams,Michael A. DeTure,Melinda McBride,Dennis W. Dickson,Leonard Petrucelli
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010810
Abstract: Tauopathies are defined by assembly of the microtubule associated protein tau into filamentous tangles and classified by the predominant tau isoform within these aggregates. The major isoforms are determined by alternative mRNA splicing of exon 10 generating tau with three (3R) or four (4R) ~32 amino acid imperfect repeats in the microtubule binding domain. In normal adult brains there is an approximately equimolar ratio of 3R and 4R tau which is altered by several disease-causing mutations in the tau gene. We hypothesized that when 4R and 3R tau isoforms are not at equimolar ratios aggregation is favored. Here we provide evidence for the first time that the combination of 3R and 4R tau isoforms results in less in vitro heparin induced polymerization than with 4R preparations alone. This effect was independent of reducing conditions and the presence of alternatively spliced exons 2 and 3 N-terminal inserts. The addition of even small amounts of 3R to 4R tau assembly reactions significantly decreased 4R assembly. Together these findings suggest that co-expression of 3R and 4R tau isoforms reduce tau filament assembly and that 3R tau isoforms inhibit 4R tau assembly. Expression of equimolar amounts of 3R and 4R tau in adult humans may be necessary to maintain proper neuronal microtubule dynamics and to prevent abnormal tau filament assembly. Importantly, these findings indicate that disruption of the normal equimolar 3R to 4R ratio may be sufficient to drive tau aggregation and that restoration of the tau isoform balance may have important therapeutic implications in tauopathies.
Progranulin in frontotemporal lobar degeneration and neuroinflammation
Zeshan Ahmed, Ian RA Mackenzie, Michael L Hutton, Dennis W Dickson
Journal of Neuroinflammation , 2007, DOI: 10.1186/1742-2094-4-7
Abstract: Progranulin (PGRN) was discovered independently by several investigators and given several different names, including granulin-epithelin precursor, proepithelin, prostate cancer (PC) cell derived growth factor and acrogranin [1]. Encoded by a single gene on chromosome 17q21 (PGRN), PGRN is a 593-amino acid, cysteine-rich protein with an estimated molecular weight of 68.5 kDa that runs at 90 kDa on standard western blots due to heavy glycosylation [2]. It contains seven granulin-like domains, which consist of highly conserved tandem repeats of a rare 12 cysteinyl motif [3,4] (Figure 1). Proteolytic cleavage of the precursor protein by extracellular proteases, such as elastase, gives rise to smaller peptide fragments termed granulins (GRNs) or epithelins [1]. These fragments range in size from 6 to 25 kDa and have been implicated in a range of biological functions [1,5].Previous work on PGRN focused on its role in embryonic development and neoplasia (reviewed elsewhere [1]). The recent discovery that mutations in PGRN cause frontotemporal lobar degeneration with ubiquitin-immunoreactive neuronal inclusions (FTLD-U) has brought renewed interest in PGRN and its functions in the central nervous system (CNS). We review what is known about PGRN in peripheral tissues during injury, repair and inflammation and explore the relevance of these properties to CNS disorders, with a focus on FTLD-U.Basal gene expression studies in mice and rats reveal widespread expression of PGRN in many different tissues, as well as in epithelial and hematopoietic cell lines [6,7]. Expression of PGRN mRNA is particularly high in epithelial cells that have a rapid turnover, such as those of the skin and gastrointestinal tract. Non-proliferating epithelia, such as lung alveolar cells, have relatively low levels of expression [6]. Epididymal cells have high PGRN expression, but are mitogenically stable, implying a pleiotropic role for PGRN. Mesenchymal tissues that lack PGRN mRNA are mitogenically r
Divergent Phenotypes in Mutant TDP-43 Transgenic Mice Highlight Potential Confounds in TDP-43 Transgenic Modeling
Simon D’Alton, Marcelle Altshuler, Ashley Cannon, Dennis W. Dickson, Leonard Petrucelli, Jada Lewis
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0086513
Abstract: The majority of cases of frontotemporal lobar degeneration and amyotrophic lateral sclerosis are pathologically defined by the cleavage, cytoplasmic redistribution and aggregation of TAR DNA binding protein of 43 kDa (TDP-43). To examine the contribution of these potentially toxic mechanisms in vivo, we generated transgenic mice expressing human TDP-43 containing the familial amyotrophic lateral sclerosis-linked M337V mutation and identified two lines that developed neurological phenotypes of differing severity and progression. The first developed a rapid cortical neurodegenerative phenotype in the early postnatal period, characterized by fragmentation of TDP-43 and loss of endogenous murine Tdp-43, but entirely lacking aggregates of ubiquitin or TDP-43. A second, low expressing line was aged to 25 months without a severe neurodegenerative phenotype, despite a 30% loss of mouse Tdp-43 and accumulation of lower molecular weight TDP-43 species. Furthermore, TDP-43 fragments generated during neurodegeneration were not C-terminal, but rather were derived from a central portion of human TDP-43. Thus we find that aggregation is not required for cell loss, loss of murine Tdp-43 is not necessarily sufficient in order to develop a severe neurodegenerative phenotype and lower molecular weight TDP-43 positive species in mouse models should not be inherently assumed to be representative of human disease. Our findings are significant for the interpretation of other transgenic studies of TDP-43 proteinopathy.
Overlapping profiles of Aβ peptides in the Alzheimer's disease and pathological aging brains
Brenda D Moore, Paramita Chakrabarty, Yona Levites, Tom L Kukar, Ann-Marie Baine, Tina Moroni, Thomas B Ladd, Pritam Das, Dennis W Dickson, Todd E Golde
Alzheimer's Research & Therapy , 2012, DOI: 10.1186/alzrt121
Abstract: Aβ was sequentially extracted with tris buffered saline (TBS), radioimmunoprecipitation buffer (RIPA), 2% sodium dodecyl sulfate (SDS) and 70% formic acid (FA) from the pre-frontal cortex of 16 AD, eight PA, and six NDC patients. These extracts were analyzed by 1) a panel of Aβ sandwich ELISAs, 2) immunoprecipitation followed by mass spectrometry (IP/MS) and 3) western blotting. These studies enabled us to asses Aβ levels and solubility, peptide profiles and oligomeric assemblies.In almost all extracts (TBS, RIPA, 2% SDS and 70% FA) the average levels of Aβ1-40, Aβ1-42, Aβ total, and Aβx-42 were greatest in AD. On average, levels were slightly lower in PA, and there was extensive overlap between Aβ levels in individual PA and AD cases. The profiles of Aβ peptides detected using IP/MS techniques also showed extensive similarity between the PA and AD brain extracts. In select AD brain extracts, we detected more amino-terminally truncated Aβ peptides compared to PA patients, but these peptides represented a minor portion of the Aβ observed. No consistent differences in the Aβ assemblies were observed by western blotting in the PA and AD groups.We found extensive overlap with only subtle quantitative differences between Aβ levels, peptide profiles, solubility, and SDS-stable oligomeric assemblies in the PA and AD brains. These cross-sectional data indicate that Aβ accumulation in PA and AD is remarkably similar. Such data would be consistent with PA representing a prodromal stage of AD or a resistance to the toxic effects of Aβ.Alzheimer's disease (AD) is characterized by large numbers of extracellular amyloid plaques with dense amyloid cores that are associated with dystrophic neurites and neuroinflammatory changes as well as intraneuronal neurofibrillary tangles. Pathological aging (PA) patients also have abundant and widespread amyloid plaques; however, these plaques have typically been described as diffuse in nature. In PA there are fewer cored plaques and there is
Development of monoclonal antibodies and quantitative ELISAs targeting insulin-degrading enzyme
Anthony DelleDonne, Naomi Kouri, Lael Reinstatler, Tomoko Sahara, Lilin Li, Ji Zhao, Dennis W Dickson, Nilufer Ertekin-Taner, Malcolm A Leissring
Molecular Neurodegeneration , 2009, DOI: 10.1186/1750-1326-4-39
Abstract: Eight monoclonal hybridoma cell lines were derived in house from mice immunized with full-length, natively folded, recombinant human IDE. The mAbs derived from these lines were shown to detect IDE selectively and sensitively by a wide range of methods. Two mAbs in particular—designated 6A1 and 6H9—proved especially selective for IDE in immunocytochemical and immunohistochemical applications. Using a variety of methods, we show that 6A1 selectively detects both human and rodent IDE, while 6H9 selectively detects human, but not rodent, IDE, with both mAbs showing essentially no cross reactivity with other proteins in these applications. Using these novel anti-IDE mAbs, we also developed sensitive and quantitative sandwich ELISAs capable of quantifying IDE levels present in human brain extracts.We succeeded in developing novel mAbs that selectively detect rodent and/or human IDE, which we have shown to be suitable for a wide range of applications, including western blotting, immunoprecipitation, immunocytochemistry, immunohistochemistry, and quantitative sandwich ELISAs. These novel anti-IDE mAbs and the assays derived from them constitute important new tools for addressing many unresolved questions about the basic biology of IDE and its role in multiple highly prevalent human diseases.Insulin-degrading enzyme (IDE; EC 3.4.24.56; a.k.a. insulysin, insulinase, insulin protease) is an atypical zinc-metalloprotease that hydrolyzes several biomedically important intermediate-sized peptide substrates, including insulin, insulin-like growth factor-2, glucagon, amylin, and the amyloid β-protein [1-3]. IDE is implicated in the pathogenesis of Alzheimer disease (AD) [4,5] and type-2 diabetes mellitus [6-8], and has also been identified as the cellular receptor for varicella zoster virus infection and cell-to-cell spread [9].Despite the clear biomedical significance of this protease, many fundamental questions about the basic biology of IDE remain unresolved, due in part to a la
Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice
Ya-Fei Xu, Yong-Jie Zhang, Wen-Lang Lin, Xiangkun Cao, Caroline Stetler, Dennis W Dickson, Jada Lewis, Leonard Petrucelli
Molecular Neurodegeneration , 2011, DOI: 10.1186/1750-1326-6-73
Abstract: To explore the pathogenic properties of the M337V mutation, we generated and characterized two mouse lines expressing human TDP-43 (hTDP-43M337V) carrying this mutation. hTDP-43M337V was expressed primarily in the nuclei of neurons in the brain and spinal cord, and intranuclear and cytoplasmic phosphorylated TDP-43 aggregates were frequently detected. The levels of TDP-43 LMW products of ~25 kDa and ~35 kDa species were also increased in the transgenic mice. Moreover, overexpression of hTDP-43M337V dramatically down regulated the levels of mouse TDP-43 (mTDP-43) protein and RNA, indicating TDP-43 levels are tightly controlled in mammalian systems. TDP-43M337V mice displayed reactive gliosis, widespread ubiquitination, chromatolysis, gait abnormalities, and early lethality. Abnormal cytoplasmic mitochondrial aggregates and abnormal phosphorylated tau were also detected in the mice.Our novel TDP-43M337V mouse model indicates that overexpression of hTDP-43M337V alone is toxic in vivo. Because overexpression of hTDP-43 in wild-type TDP-43 and TDP-43M337V mouse models produces similar phenotypes, the mechanisms causing pathogenesis in the mutant model remain unknown. However, our results suggest that overexpression of the hTDP-43M337V can cause neuronal dysfunction due to its effect on a number of cell organelles and proteins, such as mitochondria and TDP-43, that are critical for neuronal activity. The mutant model will serve as a valuable tool in the development of future studies designed to uncover pathways associated with TDP-43 neurotoxicity and the precise roles TDP-43 RNA targets play in neurodegeneration.TDP-43 is the major component of ubiquitinated inclusions in most cases of ALS and FTLD-U [1,2], and the link between TDP-43 mutations and neurodegeneration was first established in 2008 [3,4]. Autosomal dominant mutations in TARDBP, the gene encoding TDP-43, are associated with sporadic and familial ALS [3-7]. TDP-43 is a ubiquitously expressed 414-amino acid nu
Polymorphic genes of detoxification and mitochondrial enzymes and risk for progressive supranuclear palsy: a case control study
Lisa F Potts, Alex C Cambon, Owen A Ross, Rosa Rademakers, Dennis W Dickson, Ryan J Uitti, Zbigniew K Wszolek, Shesh N Rai, Matthew J Farrer, David W Hein, Irene Litvan
BMC Medical Genetics , 2012, DOI: 10.1186/1471-2350-13-16
Abstract: DNA from 553 autopsy-confirmed Caucasian PSP cases (266 females, 279 males; age at onset 68 ± 8 years; age at death 75 ± 8) from the Society for PSP Brain Bank and 425 clinical control samples (197 females, 226 males; age at draw 72 ± 11 years) from healthy volunteers were genotyped using Taqman PCR and the SequenomiPLEX Gold assay.The proportion of NAT2 rapid acetylators compared to intermediate and slow acetylators was larger in cases than in controls (OR = 1.82, p < 0.05). There were no allelic or genotypic associations with PSP for any other SNPs tested with the exception of MAPT (p < 0.001).Our results show that NAT2 rapid acetylator phenotype is associated with PSP, suggesting that NAT2 may be responsible for activation of a xenobiotic whose metabolite is neurotoxic. Although our results need to be further confirmed in an independent sample, NAT2 acetylation status should be considered in future genetic and epidemiological studies of PSP.Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian disorder. Classically, patients present with progressive postural instability and falls followed by slow and hypometric vertical saccades and eventually vertical supranuclear gaze palsy.Neuropathologically, PSP is characterized by deposits of four-repeat microtubule associated protein tau (encoded by the MAPT gene) aggregates in neurons and glia of the basal ganglia and brain-stem [1]. Additionally, there is mitochondrial dysfunction, decreased ATP levels and inflammation in the brains of PSP patients [2-4]. The MAPT H1 haplotype has been consistently reported to be associated with PSP; however, it is also common in the general population, suggesting that gene-gene or gene-environment interactions are likely required for the development of this disease [5,6]. Recently, MAPT H1 was also associated with risk of Parkinson's disease (PD) suggesting shared pathways of disease [7]. Early-onset PD and PSP can present with a similar phenotype and be misdiagn
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