The pathological significance of intracellular Abeta accumulation in vivo is not yet fully understood. To address this, we have studied transgenic rats expressing Alzheimer's-related transgenes that accumulate Abeta intraneuronally in the cerebral and hippocampal cortices but do not develop extracellular amyloid plaques. In these rats, the presence of intraneuronal Abeta is sufficient to provoke up-regulation of the phosphorylated form of extracellular-regulated kinase (ERK) 2 and its enzymatic activity in the hippocampus while no changes were observed in the activity or phosphorylation status of other putative tau kinases such as p38, glycogen synthase kinase 3, and cycline-dependent kinase 5. The increase in active phospho-ERK2 was accompanied by increased levels of tau phosphorylation at S396 and S404 ERK2 sites and a decrease in the phosphorylation of the CREB kinase p90RSK. In a water maze paradigm, male transgenic rats displayed a mild spatial learning deficit relative to control littermates. Our results suggest that in the absence of plaques, intraneuronal accumulation of Abeta peptide correlates with the initial steps in the tau-phosphorylation cascade, alterations in ERK2 signaling and impairment of higher CNS functions in male rats.