Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction.
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.
Oddo
Salvatore
S
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697, USA.
Caccamo
Antonella
A
Shepherd
Jason D
JD
Murphy
M Paul
MP
Golde
Todd E
TE
Kayed
Rakez
R
Metherate
Raju
R
Mattson
Mark P
MP
Akbari
Yama
Y
LaFerla
Frank M
FM
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*
D016229:Amyloid beta-Peptides