However, the design of the present study with a restricted number of available very old 3xTg mice does not allow more detailed biochemical and immunohistochemical analyses as well as additional behavioural testing. Such studies might include links between abnormal phosphorylation and conformational changes of tau, possibly also affecting GSK 3β known as an important enzyme for the generation of phospho-tau epitopes [65] and shown here in cells co-labelled with AT8. These

desirable efforts are mainly forced by the widely accepted crucial role of abnormal tau and tangle formation in AD and other tauopathies such as corticobasal degeneration, argyrophilic grain disease, progressive supranuclear palsy, Pick’s disease and fronto-temporal dementia (for reviews on

tauopathies see [6, 66, 67]). In AD patients, the number of CHIR-99021 nmr counted tangles post mortem correlated with the severity of dementia in lifetime [56]. Transgenic models already contributed to novel concepts for a better understanding of AD and other neurodegenerative disorders as summarized by several reviews [12, 14, 68, 69]. However, the incomplete nature of these models allows recapitulation of only a few aspects of the complexity in AD [1, 15, 70, 71]. Furthermore, models with less limitations might also settle controversies of whether deleterious effects of tau pathologies result from toxic gain-of-function by pathological tau or from critically affected tau function in the AZD8055 mw disease state [72]. Improved models might verify the proposed, partly neuroprotective role of tau phosphorylation [73]. Notably, Western blotting has revealed considerably enhanced Cytidine deaminase hippocampal GFAP levels in 7-month-old immunolesioned 3xTg versus naive mice. This might partially model the general and dramatic glial reaction as already described by Delacourte

in 1990 [74]. While fluorescence labelling also suggested enhanced gliosis associated with strong Aβ-immunoreactivity, it only allows for qualitative estimation. The observed activated glia surrounding plaques resembles the relationships of microglia and astrocytes to Aβ deposits in AD and in mouse models with age-dependent β-amyloidosis such as Tg2576 [75]. Microglia as active sensors and versatile effector cells in pathologically altered brain [76] have been reported as a driving force in plaque formation, whereas astrocytes were found as a leading factor in their degradation [77]. On the other hand, the proposed role for microglia in plaque maintenance [78] could not be confirmed by Grathwohl et al. [79]. However, microglia were found to be increasingly dysfunctional during ageing, possibly contributing to age-dependent neurodegeneration [80], which remains a promising target for therapeutic intervention.