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
Autor(en): | Shahani, Neelam Subramaniam, Srinivasa Wolf, Tobias Tackenberg, Christian Brandt, Roland |
Stichwörter: | ACTIVATED PROTEIN-KINASE; BALLOONED NEURONS; BRAIN; CELL-DEATH; DENDRITIC SPINES; DNA FRAGMENTATION; hippocampus; MICE; neurodegeneration; NEUROFIBRILLARY TANGLES; Neurosciences; Neurosciences & Neurology; PAIRED HELICAL FILAMENTS; PHOSPHORYLATION; sindbis virus; spines; tauopathy | Erscheinungsdatum: | 2006 | Herausgeber: | SOC NEUROSCIENCE | Journal: | JOURNAL OF NEUROSCIENCE | Volumen: | 26 | Ausgabe: | 22 | Startseite: | 6103 | Seitenende: | 6114 | Zusammenfassung: | 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. |
ISSN: | 02706474 | DOI: | 10.1523/JNEUROSCI.4245-05.2006 |
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