Triple-transgenic model of Alzheimer's Disease with plaques and tangles

Intracellular Aβ and synaptic dysfunction

Salvatore Oddo, Antonella Caccamo, Jason D. Shepherd, M. Paul Murphy, Todd E. Golde, Rakez Kayed, Raju Metherate, Mark P. Mattson, Yama Akbari, Frank M. LaFerla

Research output: Contribution to journalArticle

2459 Citations (Scopus)

Abstract

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 (3xTg-AD) harboring PS1M146V, APPSwe, and tauP301L transgenes. Rather than crossing independent lines, we microinjected two transgenes into single-cell embryos from homozygous PS1M146V 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 Aβ. These studies suggest a novel pathogenic role for intraneuronal Aβ with regards to synaptic plasticity. The recapitulation of salient features of AD in these mice clarifies the relationships between Aβ, synaptic dysfunction, and tangles and provides a valuable model for evaluating potential AD therapeutics as the impact on both lesions can be assessed.

Original languageEnglish
Pages (from-to)409-421
Number of pages13
JournalNeuron
Volume39
Issue number3
DOIs
StatePublished - Jul 31 2003
Externally publishedYes

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Alzheimer Disease
Neuronal Plasticity
Transgenes
Neurofibrillary Tangles
Amyloid Plaques
Embryonic Structures
Pathology
Therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Triple-transgenic model of Alzheimer's Disease with plaques and tangles : Intracellular Aβ and synaptic dysfunction. / Oddo, Salvatore; Caccamo, Antonella; Shepherd, Jason D.; Murphy, M. Paul; Golde, Todd E.; Kayed, Rakez; Metherate, Raju; Mattson, Mark P.; Akbari, Yama; LaFerla, Frank M.

In: Neuron, Vol. 39, No. 3, 31.07.2003, p. 409-421.

Research output: Contribution to journalArticle

Oddo, S, Caccamo, A, Shepherd, JD, Murphy, MP, Golde, TE, Kayed, R, Metherate, R, Mattson, MP, Akbari, Y & LaFerla, FM 2003, 'Triple-transgenic model of Alzheimer's Disease with plaques and tangles: Intracellular Aβ and synaptic dysfunction', Neuron, vol. 39, no. 3, pp. 409-421. https://doi.org/10.1016/S0896-6273(03)00434-3
Oddo, Salvatore ; Caccamo, Antonella ; Shepherd, Jason D. ; Murphy, M. Paul ; Golde, Todd E. ; Kayed, Rakez ; Metherate, Raju ; Mattson, Mark P. ; Akbari, Yama ; LaFerla, Frank M. / Triple-transgenic model of Alzheimer's Disease with plaques and tangles : Intracellular Aβ and synaptic dysfunction. In: Neuron. 2003 ; Vol. 39, No. 3. pp. 409-421.
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