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Dementia in Parkinson's Disease Correlates with α-Synuclein Pathology but Not with Cortical Astrogliosis
Simone A. van den Berge,Josta T. Kevenaar,Jacqueline A. Sluijs,Elly M. Hol
Parkinson's Disease , 2012, DOI: 10.1155/2012/420957
Abstract: Dementia is a common feature in Parkinson’s disease (PD) and is considered to be the result of limbic and cortical Lewy bodies and/or Alzheimer changes. Astrogliosis may also affect the development of dementia, since it correlates well with declining cognition in Alzheimer patients. Thus, we determined whether cortical astrogliosis occurs in PD, whether it is related to dementia, and whether this is reflected by the presence of glial fibrillary acidic protein (GFAP) and vimentin in cerebrospinal fluid (CSF). We have examined these proteins by immunohistochemistry in the frontal cortex and by Western blot in CSF of cases with PD, PD with dementia (PDD), dementia with Lewy bodies (DLB) and nondemented controls. We were neither able to detect an increase in cortical astrogliosis in PD, PDD, or DLB nor could we observe a correlation between the extent of astrogliosis and the degree of dementia. The levels of GFAP and vimentin in CSF did not correlate to the extent of astrogliosis or dementia. We did confirm the previously identified positive correlation between the presence of cortical Lewy bodies and dementia in PD. In conclusion, we have shown that cortical astrogliosis is not associated with the cognitive decline in Lewy body-related dementia. 1. Introduction Parkinson’s disease (PD) is a progressive neurological disorder characterized by motor symptoms such as tremor, bradykinesia, rigidity, and postural instability. It is associated with an almost complete degenerative loss of dopamine neurons in the substantia nigra (SN) pars compacta and the presence of Lewy bodies (LBs) and Lewy neurites (LNs). The latter pathological hallmarks initially occur, according to Braak and colleagues, in the glossopharyngeal and vagal nerves and the anterior olfactory nucleus, and thereafter spread to other brain nuclei and cortical areas [1]. This topological progression of the disease, however, is currently being critically evaluated in the field [2–4]. In any case, a major component of these LBs and LNs is an aggregated form of the presynaptic protein α-synuclein [1]. More recently, it has become apparent that cognitive dysfunction is also an important clinical component of PD. About two-third of the patients develop cognitive deficits within 3.5 years from the disease onset [5], and up to 40% of idiopathic PD patients will develop dementia (PD with dementia, PDD) based on population-based studies (reviewed in [6]). The cognitive deficits and dementia are considered to be the result of the limbic and cortical LBs [5], although the presence of Alzheimer changes, such as
Specific Human Astrocyte Subtype Revealed by Affinity Purified GFAP+1 Antibody; Unpurified Serum Cross-Reacts with Neurofilament-L in Alzheimer
Jinte Middeldorp,Simone A. van den Berge,Eleonora Aronica,Dave Speijer,Elly M. Hol
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0007663
Abstract: The human GFAP splice variants GFAPΔ164 and GFAPΔexon6 both result in a GFAP protein isoform with a unique out-of-frame carboxy-terminus that can be detected by the GFAP+1 antibody. We previously reported that GFAP+1 was expressed in astrocytes and in degenerating neurons in Alzheimer's disease brains. In this study we aimed at further investigating the neuronal GFAP+1 expression and we started by affinity purifying the GFAP+1 antibody. The purified antibody resulted in a loss of neuronal GFAP+1 signal, although other antibodies directed against the amino- and carboxy-terminus of GFAPα still revealed GFAP-immunopositive neurons, as described before. With an in-depth analysis of a western blot, followed by mass spectrometry we discovered that the previously detected neuronal GFAP+1 expression was due to cross-reactivity of the antibody with neurofilament-L (NF-L). This was confirmed by double-label fluorescent immunohistochemistry and western blotting with the unpurified GFAP+1 antibody and an antibody against NF-L. Our data imply that NF-L can accumulate in some tangle-like structures in Alzheimer brains. More importantly, the purified GFAP+1 antibody clearly revealed a specific subtype of astrocytes in the adult human brain. These large astrocytes are present throughout the brain, e.g., along the subventricular zone, in the hippocampus, in the striatum and in the spinal cord of controls, Alzheimer, and Parkinson patients. The presence of a specific GFAP-isoform suggests a specialized function of these astrocytes.
GFAPδ Expression in Glia of the Developmental and Adolescent Mouse Brain
Carlyn Mamber, Willem Kamphuis, Nina L. Haring, Nuzrat Peprah, Jinte Middeldorp, Elly M. Hol
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0052659
Abstract: Glial fibrillary acidic protein (GFAP) is the major intermediate filament (IF) protein in astrocytes. In the human brain, GFAP isoforms have unique expression patterns, which indicate that they play distinct functional roles. One isoform, GFAPδ, is expressed by proliferative radial glia in the developing human brain. In the adult human, GFAPδ is a marker for neural stem cells. However, it is unknown whether GFAPδ marks the same population of radial glia and astrocytes in the developing mouse brain as it does in the developing human brain. This study characterizes the expression pattern of GFAPδ throughout mouse embryogenesis and into adolescence. Gfapδ transcripts are expressed from E12, but immunohistochemistry shows GFAPδ staining only from E18. This finding suggests a translational uncoupling. GFAPδ expression increases from E18 to P5 and then decreases until its expression plateaus around P25. During development, GFAPδ is expressed by radial glia, as denoted by the co-expression of markers like vimentin and nestin. GFAPδ is also expressed in other astrocytic populations during development. A similar pattern is observed in the adolescent mouse, where GFAPδ marks both neural stem cells and mature astrocytes. Interestingly, the Gfapδ/Gfapα transcript ratio remains stable throughout development as well as in primary astrocyte and neurosphere cultures. These data suggest that all astroglia cells in the developing and adolescent mouse brain express GFAPδ, regardless of their neurogenic capabilities. GFAPδ may be an integral component of all mouse astrocytes, but it is not a specific neural stem cell marker in mice as it is in humans.
The ubiquitin proteasome system in glia and its role in neurodegenerative diseases
Anne H. P. Jansen,Eric A. J. Reits,Elly M. Hol
Frontiers in Molecular Neuroscience , 2014, DOI: 10.3389/fnmol.2014.00073
Abstract: The ubiquitin proteasome system (UPS) is crucial for intracellular protein homeostasis and for degradation of aberrant and damaged proteins. The accumulation of ubiquitinated proteins is a hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer’s, Parkinson’s, and Huntington’s disease, leading to the hypothesis that proteasomal impairment is contributing to these diseases. So far, most research related to the UPS in neurodegenerative diseases has been focused on neurons, while glial cells have been largely disregarded in this respect. However, glial cells are essential for proper neuronal function and adopt a reactive phenotype in neurodegenerative diseases, thereby contributing to an inflammatory response. This process is called reactive gliosis, which in turn affects UPS function in glial cells. In many neurodegenerative diseases, mostly neurons show accumulation and aggregation of ubiquitinated proteins, suggesting that glial cells may be better equipped to maintain proper protein homeostasis. During an inflammatory reaction, the immunoproteasome is induced in glia, which may contribute to a more efficient degradation of disease-related proteins. Here we review the role of the UPS in glial cells in various neurodegenerative diseases, and we discuss how studying glial cell function might provide essential information in unraveling mechanisms of neurodegenerative diseases.
Polyglutamine Expansion Accelerates the Dynamics of Ataxin-1 and Does Not Result in Aggregate Formation
Hilde A. Krol, Przemek M. Krawczyk, Klazien S. Bosch, Jacob A. Aten, Elly M. Hol, Eric A. Reits
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001503
Abstract: Background Polyglutamine expansion disorders are caused by an expansion of the polyglutamine (polyQ) tract in the disease related protein, leading to severe neurodegeneration. All polyQ disorders are hallmarked by the presence of intracellular aggregates containing the expanded protein in affected neurons. The polyQ disorder SpinoCerebellar Ataxia 1 (SCA1) is caused by a polyQ-expansion in the ataxin-1 protein, which is thought to lead to nuclear aggregates. Methodology/Principal Findings Using advanced live cell fluorescence microscopy and a filter retardation assay we show that nuclear accumulations formed by polyQ-expanded ataxin-1 do not resemble aggregates of other polyQ-expanded proteins. Instead of being static, insoluble aggregates, nuclear accumulations formed by the polyQ-expanded ataxin-1 showed enhanced intracellular kinetics as compared to wild-type ataxin-1. During mitosis, ataxin-1 accumulations redistributed equally among daughter cells, in contrast to polyQ aggregates. Interestingly, polyQ expansion did not affect the nuclear-cytoplasmic shuttling of ataxin-1 as proposed before. Conclusions/Significance These results indicate that polyQ expansion does not necessarily lead to aggregate formation, and that the enhanced kinetics may affect the nuclear function of ataxin-1. The unexpected findings for a polyQ-expanded protein and their consequences for ongoing SCA1 research are discussed.
Regulation of stearoyl-CoA desaturase-1 after central and peripheral nerve lesions
Sebastian Breuer, Katrin Pech, Armin Buss, Christoph Spitzer, Juris Ozols, Elly M Hol, Nicole Heussen, Johannes Noth, Franz-Werner Schwaiger, Andreas B Schmitt
BMC Neuroscience , 2004, DOI: 10.1186/1471-2202-5-15
Abstract: In situ hybridization and immunohistochemistry demonstrated a strong up-regulation of SCD at mRNA and protein level in regenerating neurons of the rat facial nucleus whereas non-regenerating Clarke's and Red nucleus neurons did not show an induction of this gene.This differential expression points to a functionally significant role for the SCD-1 in the process of regeneration.It is well known that damaged nerve fibers in the peripheral nervous system (PNS) have the capacity for complete regeneration followed by the restoration of appropriate synaptic connectivity and full functional recovery. However, damaged nerve fibers in the central nervous system (CNS) only demonstrate an abortive sprouting response without any functional regeneration. Up to now, little is known about the molecular programs leading to these fundamental differences. To gain insight into the molecular differences, we have compared the differentially regulated genes of axotomized PNS neurons to those of axotomized CNS neurons by differential display polymerase chain reaction [1]. In the following study, we concentrate on one clone which corresponds to the 3' end of the rat stearoyl-Coenzyme A desaturase-1 (SCD-1).The first mammalian cDNA of this enzyme was isolated in 1986 from rat liver [2]. Subsequently, two different SCD isoforms (SCD-1 and SCD-2) were identified in mouse 3T3-L1 adipocytes [3,4]. Zheng et al. identified a third SCD isoform (SCD-3) which is exclusively present in skin [5] and most recently Miyazaki et al. identified a novel heart-specific isoform (SCD4)[6].Stearoyl-CoA desaturase is responsible for the rate limiting step in the ?9-cis desaturation of a spectrum of methylene-interrupted fatty acyl-CoA substrates [7]. One of the preferred substrates, stearoyl-CoA, is desaturated, resulting in oleoyl-CoA which is further converted into its corresponding fatty acid oleate. Beside its function as an energy store in the form of triacylglycerides and its presence in biological cell mem
Identification of regeneration-associated genes after central and peripheral nerve injury in the adult rat
Andreas B Schmitt, Sebastian Breuer, Jan Liman, Armin Buss, Christiane Schlangen, Katrin Pech, Elly M Hol, Gary A Brook, Johannes Noth, Franz-Werner Schwaiger
BMC Neuroscience , 2003, DOI: 10.1186/1471-2202-4-8
Abstract: To gain insight into the molecular mechanisms underlying the process of regeneration in the nervous system, differential display polymerase chain reaction has been used to identify differentially expressed genes following axotomy of peripheral and central nerve fibers. For this purpose, axotomy induced changes of regenerating facial nucleus neurons, and non-regenerating red nucleus and Clarke's nucleus neurons have been analyzed in an intra-animal side-to-side comparison. One hundred and thirty five gene fragments have been isolated, of which 69 correspond to known genes encoding for a number of different functional classes of proteins such as transcription factors, signaling molecules, homeobox-genes, receptors and proteins involved in metabolism. Sixty gene fragments correspond to genomic mouse sequences without known function. In situ-hybridization has been used to confirm differential expression and to analyze the cellular localization of these gene fragments. Twenty one genes (~15%) have been demonstrated to be differentially expressed.The detailed analysis of differentially expressed genes in different lesion paradigms provides new insights into the molecular mechanisms underlying the process of regeneration and may lead to the identification of genes which play key roles in functional repair of central nervous tissues.Lesioned axons of the peripheral nervous system (PNS) have the capacity to undergo successful regeneration leading to complete functional recovery. In marked contrast, lesioned axons of the central nervous system (CNS) do not demonstrate any functionally significant regeneration. An important aspect underlying the opposing outcome of injured PNS and CNS neurons are the different molecular programs initiated in the axotomized neuronal cell bodies [1,2]. One important step for the eventual success or failure of a neuron to regenerate a severed axon is the expression of important regeneration-associated genes [2,3]. To date, there is currently rela
Characterization of macrophages from schizophrenia patients
Elly M. Hol,Hans C. van Mierlo,Lot D. de Witte,Manja Litjens,Miriam E. van Strien,Paul R. Ormel,René S. Kahn
- , 2017, DOI: 10.1038/s41537-017-0042-4
Abstract: The subject demographics including: sex, age, ethnicity, cannabis usage, DSM-IV-based diagnosis, and the antipsychotic medications use
A Cyclic Undecamer Peptide Mimics a Turn in Folded Alzheimer Amyloid β and Elicits Antibodies against Oligomeric and Fibrillar Amyloid and Plaques
Peter Hoogerhout,Willem Kamphuis,Humphrey F. Brugghe,Jacqueline A. Sluijs,Hans A. M. Timmermans,Janny Westdijk,Gijsbert Zomer,Claire J. P. Boog,Elly M. Hol,Germie P. J. M. van den Dobbelsteen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019110
Abstract: The 39- to 42-residue amyloid β (Aβ) peptide is deposited in extracellular fibrillar plaques in the brain of patients suffering from Alzheimer's Disease (AD). Vaccination with these peptides seems to be a promising approach to reduce the plaque load but results in a dominant antibody response directed against the N-terminus. Antibodies against the N-terminus will capture Aβ immediately after normal physiological processing of the amyloid precursor protein and therefore will also reduce the levels of non-misfolded Aβ, which might have a physiologically relevant function. Therefore, we have targeted an immune response on a conformational neo-epitope in misfolded amyloid that is formed in advance of Aβ-aggregation. A tetanus toxoid-conjugate of the 11-meric cyclic peptide Aβ(22–28)-YNGK′ elicited specific antibodies in Balb/c mice. These antibodies bound strongly to the homologous cyclic peptide-bovine serum albumin conjugate, but not to the homologous linear peptide-conjugate, as detected in vitro by enzyme-linked immunosorbent assay. The antibodies also bound—although more weakly—to Aβ(1–42) oligomers as well as fibrils in this assay. Finally, the antibodies recognized Aβ deposits in AD mouse and human brain tissue as established by immunohistological staining. We propose that the cyclic peptide conjugate might provide a lead towards a vaccine that could be administered before the onset of AD symptoms. Further investigation of this hypothesis requires immunization of transgenic AD model mice.
Transcriptome and proteome profiling of neural stem cells from the human subventricular zone in Parkinson’s disease
August B. Smit,Elly M. Hol,Emma J. van Bodegraven,Hanneke Geut,Iryna Paliukhovich,Ka Wan Li,Miriam E. van Strien,Onur Basak,Saskia M. Burm,Vanessa Donega,Wilma D. J. van de Berg
- , 2019, DOI: 10.1186/s40478-019-0736-0
Abstract: The online version of this article (10.1186/s40478-019-0736-0) contains supplementary material, which is available to authorized users
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