Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy

Tara L. Spires, Melanie Meyer-Luehmann, Edward A. Stern, Pamela J. McLean, Jesse Skoch, Paul T. Nguyen, Brian J. Bacskai, Bradley T. Hyman

Research output: Contribution to journalArticle

414 Scopus citations

Abstract

Accumulation of amyloid-β (Aβ) into senile plaques in Alzheimer's disease (AD) is a hallmark neuropathological feature of the disorder, which likely contributes to alterations in neuronal structure and function. Recent work has revealed changes in neurite architecture associated with plaques and functional changes in cortical signaling in amyloid precursor protein (APP) expressing mouse models of AD. Here we developed a method using gene transfer techniques to introduce green fluorescent protein (GFP) into neurons, allowing the investigation of neuronal processes in the vicinity of plaques. Multiphoton imaging of GFP-labeled neurons in living Tg2576 APP mice revealed disrupted neurite trajectories and reductions in dendritic spine density compared with age-matched control mice. A profound deficit in spine density (∼50%) extends ∼20 μm from plaque edges. Importantly, a robust decrement (∼25%) also occurs on dendrites not associated with plaques, suggesting widespread loss of postsynaptic apparatus. Plaques and dendrites remained stable over the course of weeks of imaging. Postmortem analysis of axonal immunostaining and colocalization of synaptophysin and postsynaptic density 95 protein staining around plaques indicate a parallel loss of presynaptic and postsynaptic partners. These results show considerable changes in dendrites and dendritic spines in APP transgenic mice, demonstrating a dramatic synaptotoxic effect of dense-cored plaques. Decreased spine density will likely contribute to altered neural system function and behavioral impairments observed in Tg2576 mice.

Original languageEnglish (US)
Pages (from-to)7278-7287
Number of pages10
JournalJournal of Neuroscience
Volume25
Issue number31
DOIs
StatePublished - Aug 3 2005

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Keywords

  • Alzheimer
  • Dendritic spine
  • Dystrophic neurite
  • Multiphoton
  • Senile plaque
  • Tg2576

ASJC Scopus subject areas

  • Neuroscience(all)

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