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ABSTRACT: The last decade has witnessed a quantum leap in our technical abilities to generate transgenic mice, up to the point that
transgenic mouse models for any aspect of normal and pathologic physiology are within reach. Most difficult to attain, and
impossible in humans, are invasive approaches in vivo, to define the molecular, biochemical and cellular functioning of the
adult central nervous system (CNS) in normal conditions. However, even more desired, at least by some, are animal models for
those neurodegenerative diseases that become increasingly devastating in the elderly. The most evident case in point is Alzheimer’s
disease (AD).
02/2008: pages 333-361;
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Methods in molecular biology (Clifton, N.J.) 02/2003; 209:333-61.
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Samir Kumar-Singh,
Ann Julliams,
Rony Nuydens,
Chantal Ceuterick,
Christine Labeur,
Sally Serneels,
Krist'l Vennekens,
Peter Van Osta, Hugo Geerts,
Bart De Strooper,
Christine Van Broeckhoven
[show abstract]
[hide abstract]
ABSTRACT: Mutations in the beta-amyloid (Abeta) sequence of the amyloid precursor protein gene (APP) present with variable disease phenotypes. While patients with the Dutch APP mutation (E693Q) have predominantly hemorrhagic strokes, Flemish APP (A692G) patients develop both strokes and Alzheimer's disease (AD). To determine whether these diverse clinical and pathological presentations are due to mutant Abeta or APP, we studied the effect of Flemish, Dutch, and wild-type Abeta/APP on phosphorylation of specific tau epitopes observed in AD. No effect was observed in differentiated SH-SY5Y cells either stably expressing APP or treated with synthetic Abeta(12-42). However, we did observe a paradoxical temporal difference in the neurotoxic potential of mutant and wild-type Abeta. While long 24-h incubation at physiological levels of Abeta (2 microM) showed a higher amount of apoptosis for Dutch Abeta, a short 2-h incubation showed elevated apoptosis for Flemish and wild-type Abeta. The altered aggregating properties of Abeta, with Dutch Abeta aggregating faster and Flemish Abeta slower than wild type, elucidated a discrete two-phase Abeta neurotoxicity. We propose here that, at least in vitro, Abeta might be neurotoxic in an initial phase due to its soluble oligomeric or other early toxic Abeta intermediate(s), which is perhaps distinct from the late neurotoxicity incurred by aggregated larger assemblies of Abeta.
Neurobiology of Disease 12/2002; 11(2):330-40. · 5.40 Impact Factor
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ABSTRACT: Protein tau, a major microtubule-binding protein in the brain, comprises six isoforms generated through alternative mRNA splicing. A dysfunctional form of mutant and normal tau is associated or implicated in the pathogenesis of several neurodegenerative disorders. The neuropathological hallmark of these tau-opathies are intraneuronal depositions of fibrillary aggregates of which neurofibrillary tangles are most common. Several distinct transgene mouse models confirmed that tau protein can cause neurodegeneration directly. This study was aimed at identifying proteins that might play a role in the cellular disturbances caused by overexpression of the longest isoform of human tau in the brain of transgenic mice. We found 34 proteins which differed in integrated intensity by a factor of at least 1.5. These proteins could be sorted into several categories. Some of the phenotypic characteristics found in the htau transgenic mice could be related to proteins found in this study. Several proteins are linked to processes involving apoptosis and neuronal death and have been discussed in papers describing neurodegenerative disorders.
PROTEOMICS 07/2002; 2(6):656-65. · 4.51 Impact Factor
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ABSTRACT: One of the landmarks of Alzheimer's disease are neurofibrillary tangles (NFT) in the brain. NFT mainly consist of a hyperphosphorylated form of the protein tau, which is responsible for stabilisation of the neuronal cytoskeleton by microtubule binding and is unable to function properly in its hyperphosphorylated form. Glycogen synthase kinase-3beta (GSK3beta) is able to phosphorylate tau in a cellular context which could play a role in the formation of these NFT. In order to learn more about the effect of GSK-3beta in the brain, two-dimensional electrophoresis patterns of cerebrum extracts of GSK3beta[S9A] transgenic mice and wild type mice were compared quantitatively. Fifty-one spots were identified as being different in integrated intensity by at least a factor 1.5. The spots were subsequently identified by mass spectrometry. Identification of several proteins linked to signal transduction pathways in which GSK3beta plays a role, indicates that our population of identified proteins includes some down stream proteins of GSK3beta. This study may contribute to filling the gaps between GSK3beta, its substrates and finally the phosphorylation of tau.
PROTEOMICS 02/2002; 2(1):94-104. · 4.51 Impact Factor
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Kurt Spittaels,
Chris Van den Haute,
Jo Van Dorpe, Hugo Geerts,
Marc Mercken,
Koen Bruynseels,
Reena Lasrado,
Kris Vandezande,
Isabelle Laenen,
Tim Boon,
Jo Van Lint,
Jacky Vandenheede,
Dieder Moechars,
Ruth Loos,
Fred Van Leuven
[show abstract]
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ABSTRACT: Protein tau filaments in brain of patients suffering from Alzheimer's disease, frontotemporal dementia, and other tauopathies
consist of protein tau that is hyperphosphorylated. The responsible kinases operating in vivo in neurons still need to be identified. Here we demonstrate that glycogen synthase kinase-3β (GSK-3β) is an effective kinase
for protein tau in cerebral neurons in vivo in adult GSK-3β and GSK-3β × human tau40 transgenic mice. Phosphorylated protein tau migrates slower during electrophoretic
separation and is revealed by phosphorylation-dependent anti-tau antibodies in Western blot analysis. In addition, its capacity
to bind to re-assembled paclitaxel (Taxol®)-stabilized microtubules is reduced, compared with protein tau isolated from mice not overexpressing GSK-3β. Co-expression
of GSK-3β reduces the number of axonal dilations and alleviates the motoric impairment that was typical for single htau40
transgenic animals (Spittaels, K., Van den Haute, C., Van Dorpe, J., Bruynseels, K., Vandezande, K., Laenen, I., Geerts, H.,
Mercken, M., Sciot, R., Van Lommel, A., Loos, R., and Van Leuven, F. (1999) Am. J. Pathol. 155, 2153–2165). Although more hyperphosphorylated protein tau is available, neither an increase in insoluble protein tau
aggregates nor the presence of paired helical filaments or tangles was observed. These findings could have therapeutic implications
in the field of neurodegeneration, as discussed.
Journal of Biological Chemistry 12/2000; 275(52):41340-41349. · 4.77 Impact Factor
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Kurt Spittaels,
Chris Van den Haute,
Jo Van Dorpe,
Koen Bruynseels,
Kris Vandezande,
Isabelle Laenen, Hugo Geerts,
Marc Mercken,
Raf Sciot,
Alfons Van Lommel,
Ruth Loos,
Fred Van Leuven
[show abstract]
[hide abstract]
ABSTRACT: Mutations in the human tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17. Some mutations, including mutations in intron 10, induce increased levels of the functionally normal four-repeat tau protein isoform, leading to neurodegeneration. We generated transgenic mice that overexpress the four-repeat human tau protein isoform specifically in neurons. The transgenic mice developed axonal degeneration in brain and spinal cord. In the model, axonal dilations with accumulation of neurofilaments, mitochondria, and vesicles were documented. The axonopathy and the accompanying dysfunctional sensorimotor capacities were transgene-dosage related. These findings proved that merely increasing the concentration of the four-repeat tau protein isoform is sufficient to injure neurons in the central nervous system, without formation of intraneuronal neurofibrillary tangles. Evidence for astrogliosis and ubiquitination of accumulated proteins in the dilated part of the axon supported this conclusion. This transgenic model, overexpressing the longest isoform of human tau protein, recapitulates features of known neurodegenerative diseases, including Alzheimer’s disease and other tauopathies. The model makes it possible to study the interaction with additional factors, to be incorporated genetically, or with other biological triggers that are implicated in neurodegeneration.
American Journal Of Pathology 01/2000; · 4.89 Impact Factor
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Samir Kumar-Singh,
Ann Julliams,
Rony Nuydens,
Chantal Ceuterick,
Christine Labeur,
Sally Serneels,
Krist'l Vennekens,
Peter Van Osta, Hugo Geerts,
Bart De Strooper,
Christine Van Broeckhoven
[show abstract]
[hide abstract]
ABSTRACT: Mutations in the β-amyloid (Aβ) sequence of the amyloid precursor protein gene (APP) present with variable disease phenotypes. While patients with the Dutch APP mutation (E693Q) have predominantly hemorrhagic strokes, Flemish APP (A692G) patients develop both strokes and Alzheimer's disease (AD). To determine whether these diverse clinical and pathological presentations are due to mutant Aβ or APP, we studied the effect of Flemish, Dutch, and wild-type Aβ/APP on phosphorylation of specific tau epitopes observed in AD. No effect was observed in differentiated SH-SY5Y cells either stably expressing APP or treated with synthetic Aβ12–42. However, we did observe a paradoxical temporal difference in the neurotoxic potential of mutant and wild-type Aβ. While long 24-h incubation at physiological levels of Aβ (2 μM) showed a higher amount of apoptosis for Dutch Aβ, a short 2-h incubation showed elevated apoptosis for Flemish and wild-type Aβ. The altered aggregating properties of Aβ, with Dutch Aβ aggregating faster and Flemish Aβ slower than wild type, elucidated a discrete two-phase Aβ neurotoxicity. We propose here that, at least in vitro, Aβ might be neurotoxic in an initial phase due to its soluble oligomeric or other early toxic Aβ intermediate(s), which is perhaps distinct from the late neurotoxicity incurred by aggregated larger assemblies of Aβ.
Neurobiology of Disease.
