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The neuropathological correlates of Alzheimer's disease (AD) include amyloid-β (Aβ) plaques and neurofibrillary tangles. To study the interaction between Aβ and tau and their effect on synaptic function, we derived a triple-transgenic model (3×Tg-AD) harboring PS1_M146V, APP_Swe, and tau_P301L transgenes. Rather than crossing independent lines, we microinjected two transgenes into single-cell embryos from homozygous PS1_M146V knockin mice, generating mice with the same genetic background. 3×Tg-AD mice progressively develop plaques and tangles. Synaptic dysfunction, including LTP deficits, manifests in an age-related manner, but before plaque and tangle pathology. Deficits in long-term synaptic plasticity correlate with the accumulation of intraneuronal Aβ. These studies suggest a novel pathogenic role for intraneuronal Aβ with regards to synaptic plasticity. The recapitulation of salient features of …