title: Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction.
abstract: The neuropathological correlates of Alzheimer's disease (AD) include amyloid-beta (Abeta) plaques and neurofibrillary tangles. To study the interaction between Abeta and tau and their effect on synaptic function, we derived a triple-transgenic model (3xTg-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. 3xTg-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 Abeta 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.
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697, USA.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oddo
authors.forename: Antonella
authors.initials: A
authors.lastname: Caccamo
authors.forename: Jason D
authors.initials: JD
authors.lastname: Shepherd
authors.forename: M Paul
authors.initials: MP
authors.lastname: Murphy
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: Rakez
authors.initials: R
authors.lastname: Kayed
authors.forename: Raju
authors.initials: R
authors.lastname: Metherate
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Yama
authors.initials: Y
authors.lastname: Akbari
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000235:genetics* / Q000473:pathology; D058225:Plaque, Amyloid / Q000235:genetics / Q000473:pathology; D013569:Synapses / Q000235:genetics* / Q000473:pathology*
chemical_list: D016229:Amyloid beta-Peptides