The relation between the two defining pathologies in AD, and their relative contribution to cognitive defects, clinical symptoms, neurodegeneration, brain atrophy and dementia Dexrazoxane hydrochloride remains. Transgenic mice have been invaluable for understanding molecular mechanisms underlying amyloid peptide generation, but amyloid mice lack two major pathological features of AD, i.e. tauopathy and neuro-degeneration. Tauopathy is pathodiagnostically linked to all AD-cases, including early-onset cases due to mutations in APP or presenilins that are by definition caused by amyloid overproduction. In an experimental model, absence of protein tau alleviated the cognitive defects inflicted by amyloid, while expressing human wild-type tau causes no or minimal tauopathy. Conversely, mice expressing mutant tau associated with familial fronto-temporal dementia recapitulate robust tauopathy. Bigenic and multiple transgenic mice expressing various combinations of mutant APP and mutant tau recapitulate the combined amyloid and taupathology of AD, but lack neurodegeneration and brain-atrophy typical for AD. Here we expressed Tau or APP, both wild-type and mutants, by adeno-associated viral vectors injected directly into the hippocampus of wild-type mice. The observed dramatic pyramidal Labetalol hydrochloride neuro-degeneration inflicted by wild-type Tau4R and by mutant Tau-P301L within weeks, contrasted with mutant APP that provoked amyloid pathology after 6 months but with only minor neurodegeneration. Importantly, tau-mediated neurodegeneration was not caused by fibrillar tau-aggregates. Most prominent were cell-cycle markers, indicating that degenerating neurons were attempting to re-entry the cell-cycle. The in vivo AAV-based models firmly support the unifying hypothesis that protein tau mediates neurodegeneration by forcing post-mitotic neurons to reenter the cell-cycle in primary and secondary tauopathies. Here we provide direct in vivo experimental evidence for protein tau-mediated hippocampal neuro-degeneration using intracerebral injection of specified adeno-associated viral vectors. The salient features of the model, based on extensive characterization, qualify them as innovative and unique in several aspects: protein tau at near-physiological protein levels invokes rapid and specific degeneration of pyramidal neurons in limbic regions. Moreover, wild-type Tau4R is 
as effective as mutant Tau.P301L which is unique, to our knowledge. Thereby AAV-tau model recapitulates, and is informative, for the majority of tauopathies that are caused by wild-type Tau4R, including all AD cases. Beclin and Atg8/LC3 are essential regulators of autophagy that mark early and mature steps of autophagosomes. The overall decrease in expression of both markers in AAV-Tau.P301L mice was evident, but also without direct temporal and spatial association with degenerating neurons. Lipofuscin was evident as intra- and extra-cellular puncta in AAV-Tau injected mice in CA pyramidal neurons and region from 3 weeks p.i. onwards, correlating with neurodegeneration and persisting in hippocampal regions after the neurons were annihilated. These apparent remnant cellular debris of degenerated hippocampal neurons might support a contribution for autophagy, but also demonstrate that the complete absence of tau-aggregates in these areas is not a technical problem, and therefore conspicuous and informative. Ultrastructurally, degenerating CA neurons presented with nuclear and cytoplasmic condensation and vacuolization, clumped chromatin and indentated or blebbing nuclear membranes.