Triple-transgenic model of Alzheimer's disease with plaques and tangles:: Intracellular Aβ and synaptic dysfunction

The neuropathological correlates of Alzheimer's disease (AD) include annyloid-beta (AD) plaques and neurofibrillary tangles. To study the interaction between AD and tau and their effect on synaptic function, we derived a triple-transgenic model (3 x Tg-AD) harboring PSM146V, 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 x 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 Abeta. These studies suggest a novel pathogenic role for intraneuronal AD with regards to synaptic plasticity. The recapitulation of salient features of AD in these mice clarifies the relationships between Abeta, synaptic dysfunction, and tangles and provides a valuable model for evaluating potential AD therapeutics as the impact on both lesions can be assessed.