Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Aß-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats: Rapid reversal by anti-Aß agents

Yingjie Qi, Igor Klyubin, Sarah C. Harney, Neng Wei Hu, William K. Cullen, Marianne K. Grant, Julia Steffen, Edward N. Wilson, Sonia Do Carmo, Stefan Remy, Martin Fuhrmann, Karen H. Ashe, A. Claudio Cuello, Michael J. Rowan

Research output: Contribution to journalArticle

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Abstract

Long before synaptic loss occurs in Alzheimer's disease significant harbingers of disease may be detected at the functional level. Here we examined if synaptic long-term potentiation is selectively disrupted prior to extracellular deposition of Aß in a very complete model of Alzheimer's disease amyloidosis, the McGill-R-Thy1-APP transgenic rat. Longitudinal studies in freely behaving animals revealed an age-dependent, relatively rapid-onset and persistent inhibition of long-term potentiation without a change in baseline synaptic transmission in the CA1 area of the hippocampus. Thus the ability of a standard 200 Hz conditioning protocol to induce significant NMDA receptor-dependent short- and long-term potentiation was lost at about 3.5 months of age and this deficit persisted for at least another 2-3 months, when plaques start to appear. Consistent with in vitro evidence for a causal role of a selective reduction in NMDA receptor-mediated synaptic currents, the deficit in synaptic plasticity in vivo was associated with a reduction in the synaptic burst response to the conditioning stimulation and was overcome using stronger 400 Hz stimulation. Moreover, intracerebroventricular treatment for 3 days with an N-terminally directed monoclonal anti- human Aß antibody, McSA1, transiently reversed the impairment of synaptic plasticity. Similar brief treatment with the BACE1 inhibitor LY2886721 or the γ-secretase inhibitor MRK-560 was found to have a comparable short-lived ameliorative effect when tracked in individual rats. These findings provide strong evidence that endogenously generated human Aß selectively disrupts the induction of long-term potentiation in a manner that enables potential therapeutic options to be assessed longitudinally at the pre-plaque stage of Alzheimer's disease amyloidosis.

Original languageEnglish (US)
Article number175
JournalActa Neuropathologica Communications
Volume2
Issue number1
DOIs
StatePublished - Jan 27 2014

Fingerprint

Transgenic Rats
Long-Term Potentiation
Alzheimer Disease
Neuronal Plasticity
Amyloidosis
N-Methyl-D-Aspartate Receptors
Amyloid Precursor Protein Secretases
Aptitude
Synaptic Transmission
Longitudinal Studies
Hippocampus
Antibodies
Conditioning (Psychology)

Keywords

  • Alzheimer's disease
  • Amyloid ß
  • Immunotherapy
  • Long-term potentiation (LTP)
  • Longitudinal
  • Secretase inhibitor
  • Transgenic rat

Cite this

Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Aß-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats : Rapid reversal by anti-Aß agents. / Qi, Yingjie; Klyubin, Igor; Harney, Sarah C.; Hu, Neng Wei; Cullen, William K.; Grant, Marianne K.; Steffen, Julia; Wilson, Edward N.; Do Carmo, Sonia; Remy, Stefan; Fuhrmann, Martin; Ashe, Karen H.; Cuello, A. Claudio; Rowan, Michael J.

In: Acta Neuropathologica Communications, Vol. 2, No. 1, 175, 27.01.2014.

Research output: Contribution to journalArticle

Qi, Yingjie ; Klyubin, Igor ; Harney, Sarah C. ; Hu, Neng Wei ; Cullen, William K. ; Grant, Marianne K. ; Steffen, Julia ; Wilson, Edward N. ; Do Carmo, Sonia ; Remy, Stefan ; Fuhrmann, Martin ; Ashe, Karen H. ; Cuello, A. Claudio ; Rowan, Michael J. / Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Aß-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats : Rapid reversal by anti-Aß agents. In: Acta Neuropathologica Communications. 2014 ; Vol. 2, No. 1.
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