title: 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.
abstract: Alzheimer's disease (AD) is characterized by progressive loss of neurons in selected brain regions, extracellular accumulations of amyloid beta, 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.
authors.affiliation: Department of Neurobiology, University of Osnabrück, 49076 Osnabrück, Germany. neelam.shahani@biologie.uni-osnabrueck.de
authors.forename: Neelam
authors.initials: N
authors.lastname: Shahani
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Subramaniam
authors.forename: Tobias
authors.initials: T
authors.lastname: Wolf
authors.forename: Christian
authors.initials: C
authors.lastname: Tackenberg
authors.forename: Roland
authors.initials: R
authors.lastname: Brandt
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D017930:Genes, Reporter; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D009924:Organ Culture Techniques; D016875:tau Proteins / Q000235:genetics*
chemical_list: D016875:tau Proteins; D049452:Green Fluorescent Proteins