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

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.