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

doi:10.1016/S0896-6273(03)00434-3

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

Producción científica: Article › revisión exhaustiva

3783 Citas (Scopus)

Resumen

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 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 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.

Idioma original	English
Páginas (desde-hasta)	409-421
Número de páginas	13
Publicación	Neuron
Volumen	39
N.º	3
DOI	https://doi.org/10.1016/S0896-6273(03)00434-3
Estado	Published - jul 31 2003

Nota bibliográfica

Funding Information:
We thank P. Caroni for the Thy1.2 expression cassette; M. Hutton for the P301L cDNA; T. Fielder for microinjection of the transgene; C. Glabe for the A11 antibody; and E. Head for advice. J.D.S. was an exchange student from the University of Otago, New Zealand, supported by an Exchange Abroad Scholarship. This work was supported by a grant from the Alzheimer's Association (F.M.L.) and by National Institutes of Health grant AG17968 (F.M.L.).

Financiación

We thank P. Caroni for the Thy1.2 expression cassette; M. Hutton for the P301L cDNA; T. Fielder for microinjection of the transgene; C. Glabe for the A11 antibody; and E. Head for advice. J.D.S. was an exchange student from the University of Otago, New Zealand, supported by an Exchange Abroad Scholarship. This work was supported by a grant from the Alzheimer's Association (F.M.L.) and by National Institutes of Health grant AG17968 (F.M.L.).

Financiadores	Número del financiador
National Institutes of Health (NIH)	AG17968
National Institute on Aging	Z01AG000312
Alzheimer's Association
University of Otago

ASJC Scopus subject areas

General Neuroscience

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10.1016/S0896-6273(03)00434-3

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title = "Triple-transgenic model of Alzheimer's Disease with plaques and tangles: Intracellular Aβ and synaptic dysfunction",

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.",

author = "Salvatore Oddo and Antonella Caccamo and Shepherd, \{Jason D.\} and Murphy, \{M. Paul\} and Golde, \{Todd E.\} and Rakez Kayed and Raju Metherate and Mattson, \{Mark P.\} and Yama Akbari and LaFerla, \{Frank M.\}",

note = "Funding Information: We thank P. Caroni for the Thy1.2 expression cassette; M. Hutton for the P301L cDNA; T. Fielder for microinjection of the transgene; C. Glabe for the A11 antibody; and E. Head for advice. J.D.S. was an exchange student from the University of Otago, New Zealand, supported by an Exchange Abroad Scholarship. This work was supported by a grant from the Alzheimer's Association (F.M.L.) and by National Institutes of Health grant AG17968 (F.M.L.).",

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AU - Oddo, Salvatore

AU - Caccamo, Antonella

AU - Shepherd, Jason D.

AU - Murphy, M. Paul

AU - Golde, Todd E.

AU - Kayed, Rakez

AU - Metherate, Raju

AU - Mattson, Mark P.

AU - Akbari, Yama

AU - LaFerla, Frank M.

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PY - 2003/7/31

Y1 - 2003/7/31

N2 - 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.

AB - 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.

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

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Nota bibliográfica

Financiación

ASJC Scopus subject areas

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