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Amyloid beta-mediated cell death of cultured hippocampal neurons reveals extensive Tau fragmentation without increased full-length tau phosphorylation.

ABSTRACT: A variety of genetic and biochemical evidence suggests that amyloid ? (A?) oligomers promote downstream errors in Tau action, in turn inducing neuronal dysfunction and cell death in Alzheimer and related dementias. To better understand molecular mechanisms involved in A?-mediated neuronal cell death, we have treated primary rat hippocampal cultures with A? oligomers and examined the resulting cellular changes occurring before and during the induction of cell death with a focus on altered Tau biochemistry. The most rapid neuronal responses upon A? administration are activation of caspase 3/7 and calpain proteases. A? also appears to reduce Akt and Erk1/2 kinase activities while increasing GSK3? and Cdk5 activities. Shortly thereafter, substantial Tau degradation begins, generating relatively stable Tau fragments. Only a very small fraction of full-length Tau remains intact after 4 h of A? treatment. In conflict with expectations based on suggested increases of GSK3? and Cdk5 activities, A? does not cause any major increases in phosphorylation of full-length Tau as assayed by immunoblotting one-dimensional gels with 11 independent site- and phospho-specific anti-Tau antibodies as well as by immunoblotting two-dimensional gels probed with a pan-Tau antibody. There are, however, subtle and transient increases in Tau phosphorylation at 3-4 specific sites before its degradation. Taken together, these data are consistent with the notion that A?-mediated neuronal cell death involves the loss of full-length Tau and/or the generation of toxic fragments but does not involve or require hyperphosphorylation of full-length Tau.

SUBMITTER: Reifert J

PROVIDER: S-EPMC3121465 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Amyloid beta-mediated cell death of cultured hippocampal neurons reveals extensive Tau fragmentation without increased full-length tau phosphorylation.

Reifert Jack J Hartung-Cranston DeeAnn D Feinstein Stuart C SC

The Journal of biological chemistry 20110411 23

A variety of genetic and biochemical evidence suggests that amyloid β (Aβ) oligomers promote downstream errors in Tau action, in turn inducing neuronal dysfunction and cell death in Alzheimer and related dementias. To better understand molecular mechanisms involved in Aβ-mediated neuronal cell death, we have treated primary rat hippocampal cultures with Aβ oligomers and examined the resulting cellular changes occurring before and during the induction of cell death with a focus on altered Tau bio ...[more]

PMID: 21482827

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Project description:The microtubule-associated protein tau aggregates into distinct neurofibrillary tangles in brains afflicted with multiple neurodegenerative diseases such as Alzheimer's disease and corticobasal degeneration (CBD). The mechanism of tau misfolding and aggregation is poorly understood. Determining the structure, dynamics, and water accessibility of tau filaments may provide insight into the pathway of tau misfolding. Here, we investigate the hydration and dynamics of the β-sheet core of heparin-fibrillized 0N4R tau using solid-state nuclear magnetic resonance spectroscopy. This β-sheet core consists of the second and third microtubule-binding repeats, R2 and R3, respectively, which form a hairpin. Water-edited two-dimensional (2D) 13C-13C and 15N-13C correlation spectra show that most residues in R2 and R3 domains have low water accessibility, indicating that this hairpin is surrounded by other proteinaceous segments. However, a small number of residues, especially S285 and S316, are well hydrated compared to other Ser and Thr residues, suggesting that there is a small water channel in the middle of the hairpin. To probe whether water accessibility correlates with protein dynamics, we measured the backbone N-H dipolar couplings of the β-sheet core. Interestingly, residues in the fourth microtubule-binding repeat, R4, show rigid-limit N-H dipolar couplings, even though this domain exhibits weaker intensities in the 2D 15N-13C correlation spectra. These results suggest that the R4 domain participates in cross-β hydrogen bonding in some of the subunits but exhibits dynamic disorder in other subunits. Taken together, these hydration and dynamics data indicate that the R2-R3 hairpin of 0N4R tau is shielded from water by other proteinaceous segments on the exterior but contains a small water pore in the interior. This structural topology has various similarities with the CBD tau fibril structure but also shows specific differences. The disorder of the R4 domain and the presence of a small water channel in the heparin-fibrillized 4R tau have implications for the structure of tau fibrils in diseased brains.

Dataset Information

Amyloid beta-mediated cell death of cultured hippocampal neurons reveals extensive Tau fragmentation without increased full-length tau phosphorylation.

Publications

Amyloid beta-mediated cell death of cultured hippocampal neurons reveals extensive Tau fragmentation without increased full-length tau phosphorylation.

Similar Datasets

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