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The Journal of Neuroscience, May 31, 2006, 26(22):6103-6114; doi:10.1523/JNEUROSCI.4245-05.2006

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Neurobiology of Disease
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

Neelam Shahani,¹ Srinivasa Subramaniam,² Tobias Wolf,¹ Christian Tackenberg,¹ and Roland Brandt¹

¹Department of Neurobiology, University of Osnabrück, 49076 Osnabrück, Germany, and ²Neuroanatomy and Interdisciplinary Center for Neurosciences, University of Heidelberg, 69120 Heidelberg, Germany

Correspondence should be addressed to Dr. Neelam Shahani or Dr. Roland Brandt, Department of Neurobiology, University of Osnabrück, Barbarastraße 11, D-49076 Osnabrück, Germany. Email: neelam.shahani{at}biologie.uni-osnabrueck.de or Brandt{at}biologie.uni-osnabrueck.de

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 algorithm-based 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.

Key words: Sindbis virus; tauopathy; hippocampus; neurodegeneration; spines; phosphorylation

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Received Oct. 5, 2005; revised April 18, 2006; accepted April 19, 2006.

Correspondence should be addressed to Dr. Neelam Shahani or Dr. Roland Brandt, Department of Neurobiology, University of Osnabrück, Barbarastraße 11, D-49076 Osnabrück, Germany. Email: neelam.shahani{at}biologie.uni-osnabrueck.de or Brandt{at}biologie.uni-osnabrueck.de

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