Assembly of paired helical filaments from mouse tau: implications for the neurofibrillary pathology in transgenic mouse models for Alzheimer's disease

Kampers, T.; Pangalos, Menelas N.; Geerts, Hugo; Wiech, Hans; Mandelkow, Eva‐Maria

doi:10.1016/s0014-5793(99)00522-0

Cited by 83 publications

(60 citation statements)

References 75 publications

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“…by carrying pro-aggregation mutations). This is consistent with our earlier observation that normal mouse Tau does not differ significantly from normal human Tau in terms of assembly properties, and that both types of Tau can be co-polymerized in suitable conditions (41).…”

Section: ␤-Structure and Aggregation In Mouse Models Of Tauopathysupporting

confidence: 93%

The β-Propensity of Tau Determines Aggregation and Synaptic Loss in Inducible Mouse Models of Tauopathy

Eckermann

Mocanu

Khlistunova

et al. 2007

Journal of Biological Chemistry

158

146

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Neurofibrillary lesions are characteristic for a group of human diseases, named tauopathies, which are characterized by prominent intracellular accumulations of abnormal filaments formed by the microtubule-associated protein Tau. The tauopathies are accompanied by abnormal changes in Tau protein, including pathological conformation, somatodendritic mislocalization, hyperphosphorylation, and aggregation, whose interdependence is not well understood. To address these issues we have created transgenic mouse lines in which different variants of full-length Tau are expressed in a regulatable fashion, allowing one to switch the expression on and off at defined time points. The Tau variants differ by small mutations in the hexapeptide motifs that control the ability of Tau to adopt a ␤-structure conformation and hence to aggregate. The "pro-aggregation" mutant ⌬K280, derived from one of the mutations observed in frontotemporal dementias, aggregates avidly in vitro, whereas the "anti-aggregation" mutant ⌬K280/PP cannot aggregate because of two ␤-breaking prolines. In the transgenic mice, the pro-aggregation Tau induces a pathological conformation and pre-tangle aggregation, even at low expression levels, the antiaggregation mutant does not. This illustrates that abnormal aggregation is primarily controlled by the molecular structure of Tau in vitro and in the organism. Both variants of Tau become mislocalized and hyperphosphorylated independently of aggregation, suggesting that localization and phosphorylation are mainly a consequence of increased concentration. These pathological changes are reversible when the expression of Tau is switched off. The pro-aggregation Tau causes a strong reduction in spine synapses.

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Section: ␤-Structure and Aggregation In Mouse Models Of Tauopathysupporting

confidence: 93%

The β-Propensity of Tau Determines Aggregation and Synaptic Loss in Inducible Mouse Models of Tauopathy

Eckermann

Mocanu

Khlistunova

et al. 2007

Journal of Biological Chemistry

158

146

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“…The unexpected observation was that human Tau RD induced pathological changes even in mouse Tau, including missorting, pathological conformation, phosphorylation, and coaggregation. This is consistent with the fact that different human and mouse Tau isoforms can coassemble in vitro (Kampers et al, 1999). The abnormal distribution and phosphorylation of mouse Tau argues that aggregation of the exogenous Tau can trigger abnormal changes in the total Tau pool (i.e., foreign Tau can "poison" host Tau).…”

Section: Coaggregation Of Tau Rd /⌬K280 With Endogenous Mouse Tausupporting

confidence: 79%

“…The uncertainty arises partly because mouse Tau does not normally form aggregates, although its assembly in vitro is indistinguishable from human Tau (Kampers et al, 1999). Secondly, full-length mouse and human Tau isoforms are difficult to discern because of their similarity and het- Figure 9.…”

Section: Coaggregation Of Tau Rd /⌬K280 With Endogenous Mouse Taumentioning

confidence: 99%

The Potential for β-Structure in the Repeat Domain of Tau Protein Determines Aggregation, Synaptic Decay, Neuronal Loss, and Coassembly with Endogenous Tau in Inducible Mouse Models of Tauopathy

Mocanu¹,

Nissen²,

Eckermann³

et al. 2008

J. Neurosci.

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272

245

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We describe two new transgenic mouse lines for studying pathological changes of Tau protein related to Alzheimer's disease. They are based on the regulatable expression of the four-repeat domain of human Tau carrying the FTDP17 (frontotemporal dementia and parkinsonism linked to chromosome 17) mutation ⌬K280 (Tau RD /⌬K280), or the ⌬K280 plus two proline mutations in the hexapeptide motifs (Tau RD /⌬K280/I277P/I308P). The ⌬K280 mutation accelerates aggregation ("proaggregation mutant"), whereas the proline mutations inhibit Tau aggregation in vitro and in cell models ("antiaggregation mutant"). The inducible transgene expression was driven by the forebrain-specific CaMKII␣ (calcium/calmodulin-dependent protein kinase II␣) promoter. The proaggregation mutant leads to Tau aggregates and tangles as early as 2-3 months after gene expression, even at low expression (70% of endogenous mouse Tau). The antiaggregation mutant does not aggregate even after 22 months of gene expression. Both mutants show missorting of Tau in the somatodendritic compartment and hyperphosphorylation in the repeat domain [KXGS motifs, targets of the kinase MARK (microtubule affinity regulating kinase)]. This indicates that these changes are related to Tau expression rather than aggregation. The proaggregation mutant causes astrogliosis, loss of synapses and neurons from 5 months of gene expression onward, arguing that Tau toxicity is related to aggregation. Remarkably, the human proaggregation mutant Tau RD coaggregates with mouse Tau, coupled with missorting and hyperphosphorylation at multiple sites. When expression of proaggregation Tau RD is switched off, soluble and aggregated exogenous Tau RD disappears within 1.5 months. However, tangles of mouse Tau, hyperphosphorylation, and missorting remain, suggesting an extended lifetime of aggregated wild-type Tau once a pathological conformation and aggregation is induced by a proaggregation Tau species.

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“…Murine tau can be phosphorylated and form PHFs in vitro (Kampers et al, 1999). We find that restraint provokes tau-P at each of seven epitopes examined, all but one of whose responses is differentially modulated by CRFR status.…”

Section: Relationship To Previous Studiesmentioning

confidence: 79%

Corticotropin-Releasing Factor Receptors Differentially Regulate Stress-Induced Tau Phosphorylation

Rissman¹,

Lee²,

Vale³

et al. 2007

Journal of Neuroscience

135

147

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Hyperphosphorylation of the microtubule-associated protein tau is a key event in the development of Alzheimer's disease (AD) neuropathology. Acute stress can induce hippocampal tau phosphorylation (tau-P) in rodents, but the mechanisms and pathogenic relevance of this response are unclear. Here, we find that hippocampal tau-P elicited by an acute emotional stressor, restraint, was not affected by preventing the stress-induced rise in glucocorticoids but was blocked by genetic or pharmacologic disruption of signaling through the type 1 corticotropin-releasing factor receptor (CRFR1). Conversely, these responses were exaggerated in CRFR2-deficient mice. Parallel CRFR dependence was seen in the stress-induced activation of specific tau kinases. Repeated stress exposure elicited cumulative effects on tau-P and its sequestration in an insoluble, and potentially pathogenic, form. These findings support differential regulatory roles for CRFRs in an AD-relevant form of neuronal plasticity and may link datasets documenting alterations in the CRF signaling system in AD and implicating chronic stress as a risk factor in age-related neurological disorders.

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Assembly of paired helical filaments from mouse tau: implications for the neurofibrillary pathology in transgenic mouse models for Alzheimer's disease

Cited by 83 publications

References 75 publications

The β-Propensity of Tau Determines Aggregation and Synaptic Loss in Inducible Mouse Models of Tauopathy

The β-Propensity of Tau Determines Aggregation and Synaptic Loss in Inducible Mouse Models of Tauopathy

The Potential for β-Structure in the Repeat Domain of Tau Protein Determines Aggregation, Synaptic Decay, Neuronal Loss, and Coassembly with Endogenous Tau in Inducible Mouse Models of Tauopathy

Corticotropin-Releasing Factor Receptors Differentially Regulate Stress-Induced Tau Phosphorylation

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