Modeling of Tau-Mediated Synaptic and Neuronal Degeneration in Alzheimer's Disease
Figure 2
Protein Tau is activated by and therefore downstream of amyloid pathology. (a) Tau.P301L transgenic mice [36] were injected intracerebrally at age 1.5 months with either AAV-APP.SLA vector (10e8 tu) or with AAV-EGFP as control. At 6 months p.i. the expression of APP.SLA, unlike EGFP, led to formation of amyloid aggregates and plaques, as shown by histochemical staining with X34 (lower left panel). The mutant APP.SLA also strongly increased the phosphorylation of transgenic Tau.P301L resulting in the formation of neurofibrillary tangles already at this age of the Tau.P301L mice in pyramidal neurons of CA1: immunohistochemistry with Mab AT180 specific for phospho-T231-Tau (upper panels), Mab MC1 (conformational Tau-epitope) (middle panel left) and Mab AT100 (phospho-S212/T214) (middle panel right). Remarkably, the amyloid plaques and Tau pathological aggregates coexist in AAV-APP.SLA-injected Tau.P301L mice without causing appreciable neurodegeneration. (b) Intracerebral injection of AAV-Tau.P301L (10e8 tu) in wild-type mice produced extensive neurodegeneration of CA1 pyramidal neurons as shown before [11]. Aggregates of Tau or tangles were very rare although they can form in these neurons in the experimental conditions, as shown histochemically with compound X34 as sensitive probe for -sheeted aggregated protein [12, 14]. Clearly, the paucity of tangles cannot explain the extensive neuronal cell death. Degenerating neurons share morphological features of necrosis and autophagy, with extensive vacuolization as demonstrated histochemically by toluidin blue staining (bottom panel).
