Cerebrospinal Fluid Tissue Transglutaminase as a Biochemical Marker for Alzheimer's Disease

Bonelli, Raphael M.; Aschoff, A.; Niederwieser, Gerald; Heuberger, Clemens; Jirikowski, Gustaf

doi:10.1006/nbdi.2002.0535

Cited by 54 publications

(39 citation statements)

References 37 publications

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“…The second transglutaminasemediated cross-linking step is also linked to A␤ and the pathogenesis of AD, because cerebral microinjection of A␤ or enhanced formation of (aggregated) A␤ triggered the activation/induction of transglutaminase in mice (see the accompanying article (26)). In agreement with a role of A␤ in inducing transglutaminase is the observation that transglutaminase activity is elevated in the brains of AD patients (22,23).…”

supporting

confidence: 72%

Dominant Negative AT2 Receptor Oligomers Induce G-protein Arrest and Symptoms of Neurodegeneration

AbdAlla

Lother

Missiry

et al. 2009

Journal of Biological Chemistry

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Neurodegeneration in Alzheimer's disease (AD) correlates with dysfunction of signaling mediated by G␣ q/11 . Nondissociable angiotensin II AT 2 receptor oligomers are linked to the impaired G␣ q/11 -stimulated signaling of AD patients and transgenic mice with AD-like symptoms. To further analyze the role of AT 2 receptor oligomers, we induced the formation of AT 2 oligomers in an in vitro cell system. Similarly as in vivo, sequential oxidative and transglutaminase-dependent cross-linking steps triggered the formation of AT 2 oligomers in vitro. Elevated reactive oxygen species mediated oxidative cross-linking of AT 2 monomers to dimers involving tyrosine residues located at putative interreceptor contact sites of the cytoplasmic loop connecting transmembrane helices III/IV. Cross-linked AT 2 dimers were subsequently a substrate of activated transglutaminase-2, which targeted the carboxyl terminus of AT 2 dimers, as assessed by truncated and chimeric AT 2 receptors, respectively. AT 2 oligomers acted as dominant negative receptors in vitro by mediating G␣ q/11 protein sequestration and G␣ q/11 protein arrest. The formation of AT 2 oligomers and G-protein dysfunction could be suppressed in vitro and in vivo by an AT 2 receptor mutant. Inhibition of AT 2 oligomerization upon stereotactic expression of the AT 2 receptor mutant revealed that G␣ q/11 -sequestering AT 2 oligomers enhanced the development of neurodegenerative symptoms in the hippocampus of transgenic mice with AD-like pathology. Thus, AT 2 oligomers inducing G␣ q/11 arrest are causally involved in inducing symptoms of neurodegeneration.Dysfunction of G␣ q/11 is a characteristic feature of AD 2 patients and transgenic mice with AD-like symptoms (see the accompanying article (26) and Refs. 1-5). The G␣ q/11 -protein defect is a well established hallmark of clinical AD (5). However, the pathophysiological role of the G-protein defect is barely understood. A direct relationship between G␣ q/11 dysfunction and the pathogenesis of AD leading to neurodegeneration and dementia is suggested by the important role of G␣ q/11 proteins in neuronal survival and memory (6, 7). In addition, many of the cognition-enhancing effects of acetylcholine are mediated by the G␣ q/11 -coupled muscarinic receptors (8). The M 1 receptor is a major target of G␣ q/11 dysfunction of AD patients and mice, and impaired G␣ q/11 -coupling of M 1 receptors correlates with disease severity (5).To better understand the pathophysiological function of the G-protein defect in AD, we analyzed the mechanism accounting for the G-protein defect in AD. In the first article (26), we identified cross-linked AT 2 receptor oligomers in the brains of AD patients and transgenic mice with AD-like symptoms. Coenrichment studies showed that AT 2 receptor oligomers resembled dominant negative receptors by sequestering G␣ q/11 in the absence of agonist. The cross-linked AT 2 receptors were directly linked to the progression of AD, because (aggregated) amyloid ␤ (A␤) triggered AT 2 oligomerization in vivo in a...

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supporting

confidence: 72%

Dominant Negative AT2 Receptor Oligomers Induce G-protein Arrest and Symptoms of Neurodegeneration

AbdAlla

Lother

Missiry

et al. 2009

Journal of Biological Chemistry

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“…It has been reported that TG activity is significantly elevated in the affected cerebral regions in Alzheimer disease, Huntington disease and supranuclear palsy (Jeitner et al, 2009). In addition, increased TG2 protein is observed in the cerebrospinal fluid of Alzheimer disease (Bonelli et al, 2002) and Parkinson disease subjects (Vermes et al, 2004). It is likely that in addition to SCA TG6 may be also involved in the development of other neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Distribution of Transglutaminase 6 in the Central Nervous System of Adult Mice

Liu

Tang

Lan

et al. 2013

The Anatomical Record

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Our previous study identified a new form of spinocerebellar ataxia (SCA), in which mutations in the gene coding for transglutaminase 6 (TG6) were suggested to be causative. However, the data concerning cellular distribution of TG6 in the brain is still fragmentary. Therefore, we now report a comprehensive immunohistochemical examination of the expression profile of TG6 in adult mouse brain. TG6 was abundantly expressed in the septal region, basal ganglia, hypothalamus and brainstem. Notably, numerous TG6-positive neurons were found in the key brain regions involved in regulating locomotion activity, including the globus pallidus, subthalamic nucleus, substantia nigra, cerebellum, some precerebellar nuclei, and spinal motor neurons. Double immunostaining showed that the vast majority of TG6-positive neurons in the reticular nigra were GABAergic and those in the compact nigra were not dopaminergic. In addition, double staining for TG6 with either anti-NeuN or glial fibrillary acidic protein (GFAP) antibodies demonstrated exclusive NeuN-TG6 co-localization. This study presents a comprehensive overview of TG6 expression in the mouse brain, and provides insight for investigating the role of TG6 in the development of SCA. Anat Rec, 296:1576Rec, 296: -1587Rec, 296: , 2013. V C 2013 Wiley Periodicals, Inc.Key words: spinocerebellar ataxia; transglutaminase 6; immunohistochemistry; brain; distribution Abbreviations used: CNS 5 central nervous system; GABA 5 gammaaminobutyric acid; GAD67 5 glutamate acid decarboxylase 67; GFAP 5 glial fibrillary acidic protein; GFP 5 green fluorescent protein; NeuN 5 neuron specific nuclear protein; SCA 5 spinocerebellar ataxia; TGM 5 transglutaminase; TH 5 tyrosine hydroxylase.

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“…Increased TGase activity appears to coincide with AD pathology (12) and cerebrospinal fluid analysis for TGase levels (9), as well as changes in A␤ concentration, and particular A␤ peptide fragment patterns have been suggested as useful biomarkers in AD (17).…”

mentioning

confidence: 99%

Tissue Transglutaminase-mediated Glutamine Deamidation of β-Amyloid Peptide Increases Peptide Solubility, Whereas Enzymatic Cross-linking and Peptide Fragmentation May Serve as Molecular Triggers for Rapid Peptide Aggregation

Schmid

Condemi

Tuchscherer

et al. 2011

Journal of Biological Chemistry

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Tissue transglutaminase (TGase) has been implicated in a number of cellular processes and disease states, where the enzymatic actions of TGase may serve in both, cell survival and apoptosis. To date, the precise functional properties of TGase in cell survival or cell death mechanisms still remain elusive. TGasemediated cross-linking has been reported to account for the formation of insoluble lesions in conformational diseases. We report here that TGase induces intramolecular cross-linking of ␤-amyloid peptide (A␤), resulting in structural changes of monomeric A␤. Using high resolution mass spectrometry (MS) of cross-linked A␤ peptides, we observed a shift in mass, which is, presumably associated with the loss of NH 3 due to enzymatic transamidation activity and hence intramolecular peptide cross-linking. We have observed that a large population of A␤ monomers contained an 0.984 Da increase in mass at a glutamine residue, indicating that glutamine 15 serves as an indispensable substrate in TGase-mediated deamidation to glutamate 15. We provide strong analytical evidence on TGasemediated A␤ peptide dimerization, through covalent intermolecular cross-linking and hence the formation of A␤ 1-40 dimers. Our in depth analyses indicate that TGase-induced post-translational modifications of A␤ peptide may serve as an important seed for aggregation.

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Cerebrospinal Fluid Tissue Transglutaminase as a Biochemical Marker for Alzheimer's Disease

Cited by 54 publications

References 37 publications

Dominant Negative AT2 Receptor Oligomers Induce G-protein Arrest and Symptoms of Neurodegeneration

Dominant Negative AT2 Receptor Oligomers Induce G-protein Arrest and Symptoms of Neurodegeneration

Distribution of Transglutaminase 6 in the Central Nervous System of Adult Mice

Tissue Transglutaminase-mediated Glutamine Deamidation of β-Amyloid Peptide Increases Peptide Solubility, Whereas Enzymatic Cross-linking and Peptide Fragmentation May Serve as Molecular Triggers for Rapid Peptide Aggregation

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