Abnormally phosphorylated tau protein in Alzheimer's disease: Heterogeneity of individual regional distribution and relationship to clinical severity

Holzer, Max; Holzapfel, H.; Zedlick, Dyrk; Brückner, Martina K.; Arendt, Thomas

doi:10.1016/0306-4522(94)90546-0

Cited by 79 publications

(35 citation statements)

References 96 publications

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“…Thereby, a condition is generated that in the adult human brain is associated with aggregation of tau protein into paired helical filaments (PHFs), as observed in Alzheimer's disease and other tauopathies (20,63,64,82,83,111,169). During torpor phases of hibernation, tau is highly phosphorylated, containing a number of PHF-like epitopes.…”

Section: Reversible Protein Phosphorylation and The Microtubule-assocmentioning

confidence: 99%

Neuronal plasticity in hibernation and the proposed role of the microtubule-associated protein tau as a “master switch” regulating synaptic gain in neuronal networks

Arendt

Bullmann

2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Arendt T, Bullmann T. Neuronal plasticity in hibernation and the proposed role of the microtubule-associated protein tau as a "master switch" regulating synaptic gain in neuronal networks. Am J Physiol Regul Integr Comp Physiol 305: R478 -R489, 2013. First published July 13, 2013 doi:10.1152/ajpregu.00117.2013.-The present paper provides an overview of adaptive changes in brain structure and learning abilities during hibernation as a behavioral strategy used by several mammalian species to minimize energy expenditure under current or anticipated inhospitable environmental conditions. One cellular mechanism that contributes to the regulated suppression of metabolism and thermogenesis during hibernation is reversible phosphorylation of enzymes and proteins, which limits rates of flux through metabolic pathways. Reversible phosphorylation during hibernation also affects synaptic membrane proteins, a process known to be involved in synaptic plasticity. This mechanism of reversible protein phosphorylation also affects the microtubule-associated protein tau, thereby generating a condition that in the adult human brain is associated with aggregation of tau protein to paired helical filaments (PHFs), as observed in Alzheimer's disease. Here, we put forward the concept that phosphorylation of tau is a neuroprotective mechanism to escape NMDA-mediated hyperexcitability of neurons that would otherwise occur during slow gradual cooling of the brain. Phosphorylation of tau and its subsequent targeting to subsynaptic sites might, thus, work as a kind of "master switch," regulating NMDA receptor-mediated synaptic gain in a wide array of neuronal networks, thereby enabling entry into torpor. If this condition lasts too long, however, it may eventually turn into a pathological trigger, driving a cascade of events leading to neurodegeneration, as in Alzheimer's disease or other "tauopathies".Alzheimer's disease; neurodegeneration; neuroprotection; neuronal plasticity; protein phosphorylation; tauopathies Seasonal Brain Plasticity Might Be a Widespread PhenomenonANIMALS LIVING IN ENVIRONMENTS with daily or seasonal rhythms have developed different strategies to coordinate endogenous processes with ambient conditions. To optimize their energy balance under conditions of restricted availability of food and increased costs for temperature regulation, animals can either reduce the expense for foraging or the need of foraging (96). The expense for foraging can be reduced by food storing or escaping a cold climate by migration. Alternatively, hibernation is a powerful strategy to reduce the metabolic costs of daily activity. All of these aforementioned strategies to optimize energy expenditure are associated with plastic adaptive changes both at the level of behavior and brain structure.The seasonal modulation of food-storing behavior (33,177,178,182) or migration (17) in birds has been shown to require special spatial learning abilities, which are paralleled by seasonal changes in neuronal structure. These cyclic changes in size and mo...

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Section: Reversible Protein Phosphorylation and The Microtubule-assocmentioning

confidence: 99%

Neuronal plasticity in hibernation and the proposed role of the microtubule-associated protein tau as a “master switch” regulating synaptic gain in neuronal networks

Arendt

Bullmann

2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…This hyperphosphorylated Tau protein, which shows reduced affinity toward microtubules, eventually sequesters into neurofibrillary tangles (6 -7). The distribution of neurofibrillary tangles correlates well with the loss of neurons and cognitive dysfunction in AD (8,9). The conversion from native soluble Tau to aggregated Tau seems to involve conformational changes from a random coil to a ␤-sheet structure and the assembly of ␤-sheet-containing Tau monomers into filaments (10 -12).…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Tau Oligomers Impair Artificial Membrane Integrity and Cellular Viability

Flach

Hilbrich

Schiffmann

et al. 2012

Journal of Biological Chemistry

168

151

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Background: Tau aggregation is a multistep process. The identity of Tau species compromising cell viability remains largely unknown. Results: Analysis of Tau aggregation dynamic identifies oligomeric Tau aggregates as toxic species that impair viability. Conclusion: Membrane leakage induced by oligomeric Tau is a mechanism for toxicity. Significance: Tau belongs to the class of amyloidogenic proteins that share a common toxicity-mediating mechanism.

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“…A good correlation between the amount of hyperphosphorylated tau and the clinical severity of AD patients has been demonstrated (Holzer et al, 1994). Site-specific phosphorylation of tau can be regulated by concerted and sequential action of many protein kinases and phosphatases (Iqbal et al, 2005;Stoothoff and Johnson, 2005).…”

Section: Introductionmentioning

confidence: 99%

Tau Aggregation and Progressive Neuronal Degeneration in the Absence of Changes in Spine Density and Morphology after Targeted Expression of Alzheimer's Disease-Relevant Tau Constructs in Organotypic Hippocampal Slices

Shahani¹,

Subramaniam²,

Wolf³

et al. 2006

J. Neurosci.

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Alzheimer's disease (AD) is characterized by progressive loss of neurons in selected brain regions, extracellular accumulations of amyloid ␤, and intracellular fibrils containing hyperphosphorylated tau. Tau mutations in familial tauopathies confirmed a central role of tau pathology; however, the role of tau alteration and the sequence of tau-dependent neurodegeneration in AD remain elusive. Using Sindbis virus-mediated expression of AD-relevant tau constructs in hippocampal slices, we show that disease-like tau modifications affect tau phosphorylation at selected sites, induce Alz50/MC1-reactive pathological tau conformation, cause accumulation of insoluble tau, and induce region-specific neurodegeneration. Live imaging demonstrates that tau-dependent degeneration is associated with the development of a "ballooned" phenotype, a distinct feature of cell death. Spine density and morphology is not altered as judged from algorithmbased evaluation of dendritic spines, suggesting that synaptic integrity is remarkably stable against tau-dependent degeneration. The data provide evidence that tau-induced cell death involves apoptotic as well as nonapoptotic mechanisms. Furthermore, they demonstrate that targeted expression of tau in hippocampal slices provides a novel model to analyze tau modification and spatiotemporal dynamics of tau-dependent neurodegeneration in an authentic CNS environment.

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Abnormally phosphorylated tau protein in Alzheimer's disease: Heterogeneity of individual regional distribution and relationship to clinical severity

Cited by 79 publications

References 96 publications

Neuronal plasticity in hibernation and the proposed role of the microtubule-associated protein tau as a “master switch” regulating synaptic gain in neuronal networks

Neuronal plasticity in hibernation and the proposed role of the microtubule-associated protein tau as a “master switch” regulating synaptic gain in neuronal networks

Tau Oligomers Impair Artificial Membrane Integrity and Cellular Viability

Tau Aggregation and Progressive Neuronal Degeneration in the Absence of Changes in Spine Density and Morphology after Targeted Expression of Alzheimer's Disease-Relevant Tau Constructs in Organotypic Hippocampal Slices

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