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ABSTRACT: Alzheimer's disease (AD) is characterized by extracellular beta-amyloid (Abeta(42))-containing plaques and intracellular neurofibrillary tangles. The latter are composed of hyperphosphorylated filamentous aggregates of the microtubule-associated protein tau. Previously we demonstrated pathological interactions between these two histopathological hallmarks using human SH-SY5Y neuroblastoma cells overexpressing wild-type and mutant forms of human tau. Exposure to pre-aggregated forms of Abeta(42) caused both the formation of AD-like tau-containing filaments and a decreased solubility of tau, both of which were prevented by mutating the S422 phospho-epitope of tau. Here, we expressed additional tau mutants in SH-SY5Y cells to assess the role of phosphorylation and cleavage sites of tau in tau aggregation. We found that the Abeta(42)-mediated decrease in tau solubility depends on the interplay of distinct phospho-epitopes of tau and not only on phosphorylation of the S422 epitope.
Biochemical and Biophysical Research Communications 01/2006; 337(4):1097-101. · 2.48 Impact Factor
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ABSTRACT: Of all forms of dementia, Alzheimer's disease is the most prevalent. It is histopathologically characterized by beta-amyloid-containing plaques, tau-containing neurofibrillary tangles, reduced synaptic density and neuronal loss in selected brain areas. For the rare familial forms of Alzheimer's disease, pathogenic mutations have been identified in both the gene encoding the precursor of the Abeta peptide, APP, itself and in the presenilin genes which encode part of the APP-protease complex. For the more frequent sporadic forms of Alzheimer's disease, the pathogenic trigger has not been unambiguously identified. Whether Abeta is again the main cause remains to be heavily discussed. In a related disorder termed frontotemporal dementia, which is characterized by tangles in the absence of beta-amyloid deposition, mutations have been identified in tau which also lead to neurodegeneration and dementia. For Alzheimer's disease the existence of familial forms lead to the proposition of the amyloid cascade hypothesis, which claims that beta-amyloid causes or enhances the tangle pathology. In this review, we describe tau transgenic mouse models in which aspects of the tau-associated pathology, including tangle formation, has been achieved. Moreover, tau transgenic mouse and tissue-culture models were used to test the amyloid cascade hypothesis. In addition, we discuss alternative hypotheses to explain the sporadic forms. The animal and tissue-culture models will provide insight into the underlying biochemical mechanisms of tau aggregation and nerve cell degeneration. These mechanisms may be partially shared between sporadic Alzheimer's disease, the familial forms and frontotemporal dementia. Eventually, Alzheimer's disease may be redefined based on biochemical events rather than phenotype.
International Journal of Developmental Neuroscience 12/2004; 22(7):453-65. · 2.42 Impact Factor
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ABSTRACT: Neurofibrillary tangles, insoluble protein deposits composed of filamentous tau aggregates, are neuropathological hallmarks of Alzheimer's disease and familial frontotemporal dementia (FTDP-17). Transgenic mice expressing the FTDP-17 mutation P301L of tau recapitulate key features of the human pathology, that is, tau proteins aggregate and neurofibrillary tangles begin to appear in the amygdala at 6 months of age. To detect early signs of tau aggregate-associated changes, we investigated behavioral alterations and cognitive deficits in such mice using an amygdala-specific test battery for anxiety-related and cognitive behavior. P301L mice had anxiety levels not different from wild-types, but their exploratory behavior was significantly increased. Acquisition of a fear response to tone and context as well as taste aversion was comparable to wild-types. However, extinction of a conditioned taste aversion was significantly accelerated. We conclude that already aggregation of tau proteins not yet accompanied by massive formation of neurofibrillary tangles causes selective behavioral deficits.
Neurobiology of Disease 05/2004; 15(3):500-9. · 5.40 Impact Factor
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ABSTRACT: The CAmbridge Neuropsychological Test Automated Battery (CANTAB) is a computerised battery of neuropsychological tests presented as stimuli on a touch-sensitive computer screen that has been used to assess a wide range of cognitive functions in neuropsychiatric patients, healthy volunteers, and species of non-human primate, primarily the rhesus macaque. The common marmoset is a small-bodied, tractable simian primate that breeds well under laboratory conditions. This primate has been quite extensively studied in terms of its abilities and limitations with respect to appetitive cognitive conditioning. However, the CANTAB versions of sustained/divided attention and working memory tasks have to-date not been studied in the marmoset. Here we describe adult marmoset performance on the CANTAB five-choice serial reaction time task, a delayed match-to-position task, and a task derived from the CANTAB visuo-spatial paired associates learning task that constituted two, concurrent delayed match-to-position tasks. The acquisition and stable longitudinal performance of these tasks provide strong evidence that the marmoset, in addition to the macaque, can be the species of choice for CANTAB-based drug and lesion studies of cognitive function, using tasks similar to those deployed in the study of human cognition and diagnosis of neuropsychiatric disorders.
Cognitive Brain Research 05/2004; 19(2):123-37. · 3.77 Impact Factor
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ABSTRACT: Many proteins that are implicated in human disease are posttranslationally modified. This includes the microtubule-associated protein tau that is deposited in a hyperphosphorylated form in brains of Alzheimer's disease patients. The focus of this review article is on the physiological and pathological phosphorylation of tau; the relevance of aberrant phosphorylation for disease; the role of kinases and phosphatases in this process; its modeling in transgenic mice, flies, and worms; and implications of phosphorylation for therapeutic intervention.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.
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ABSTRACT: Alzheimer’s disease (AD) is characterized by extracellular β-amyloid (Aβ42)-containing plaques and intracellular neurofibrillary tangles. The latter are composed of hyperphosphorylated filamentous aggregates of the microtubule-associated protein tau. Previously we demonstrated pathological interactions between these two histopathological hallmarks using human SH-SY5Y neuroblastoma cells overexpressing wild-type and mutant forms of human tau. Exposure to pre-aggregated forms of Aβ42 caused both the formation of AD-like tau-containing filaments and a decreased solubility of tau, both of which were prevented by mutating the S422 phospho-epitope of tau. Here, we expressed additional tau mutants in SH-SY5Y cells to assess the role of phosphorylation and cleavage sites of tau in tau aggregation. We found that the Aβ42-mediated decrease in tau solubility depends on the interplay of distinct phospho-epitopes of tau and not only on phosphorylation of the S422 epitope.
Biochemical and Biophysical Research Communications.
