We have previously reported that double-transgenic APPSW/TauVLW mice show enhanced amyloid deposition, stronger tau hyperphosphorylation, increased sarkosyl tau polymers, and wider tau filaments when compared to simple mutant models. To validate these transgenic mice as models of Alzheimer disease pathology, in the present study we analyze tau phosphorylation at 12E8 and AT-8 epitopes in amyloid plaques. In APPSW mice, phospho-tau in plaque-associated neurites suggests a local direct effect of plaque-amyloid (and/or APPSW) on tau phosphorylation. In vitro, attempts to identify which kinases are induced by fibrillar amyloid reveal to Protein Kinase C as responsible for phosphorylation at the 12E8 epitope. TauVLW mice, without plaques, show increased tau phosphorylation at the 12E8 epitope, particularly in pyramidal neurons. APPSW/TauVLW mice show earlier and stronger 12E8 tau phosphorylation. Ultrastructurally, the same two types of neurites are found in plaques from APPSW/TauVLW and Alzheimer disease (AD) brains: (a) dystrophic giant neurites filled with degenerating organelles and/or phospho-tau-positive filaments and (b) non-dystrophic phospho-tau-positive small punctiform neurites. Both types of plaque-associated neurites are AT-8 positive in APPSW/TauVLW mice and AD, but 12E8-positive dystrophic neurites are only detected in AD. We conclude that the simultaneous presence of human mutated TauVLW and plaque-amyloid (and/or APPSW) potentiates and anticipates tau phosphorylation at the 12E8 epitope, intensifying pyramidal neuron immunostaining and tau filament formation in this double-transgenic model. Thus, the APPSW/TauVLW mouse is a useful model to study neuritic plaques, since they reproduce most of the characteristics that these structures have in AD.