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.
Dendritic Spine Abnormalities in Amyloid Precursor Protein Transgenic Mice Demonstrated by Gene Transfer and Intravital Multiphoton Microscopy
T. Spires,Melanie Meyer‐Luehmann,E. Stern,P. McLean,J. Skoch,P. T. Nguyen,B. Bacskai,B. Hyman
Published 2005 in Journal of Neuroscience
ABSTRACT
PUBLICATION RECORD
- Publication year
2005
- Venue
Journal of Neuroscience
- Publication date
2005-08-03
- Fields of study
Biology, Medicine
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- amyloid plaques
Dense extracellular deposits of amyloid-β in brain tissue that served as the local anatomical reference for the imaging analyses.
Aliases: plaques, dense-cored plaques
- dendritic spine density
The number of dendritic spines per unit dendrite length used as a measure of postsynaptic structure.
Aliases: spine density
- gene transfer
A technique used here to deliver genetic material into neurons so they could express a fluorescent marker.
Aliases: genetic transfer
- green fluorescent protein
A fluorescent reporter protein expressed in neurons to label their processes for imaging.
Aliases: GFP
- intravital multiphoton microscopy
A live-imaging method used to visualize fluorescently labeled neuronal structures in intact mouse brain tissue.
Aliases: multiphoton imaging, two-photon microscopy
- synaptophysin and postsynaptic density 95 protein staining
Combined immunostaining for a presynaptic marker and a postsynaptic scaffold protein used to assess synaptic elements around plaques.
Aliases: synaptophysin, PSD95 staining, PSD-95 staining
- tg2576 app mice
An amyloid precursor protein transgenic mouse line used as the experimental Alzheimer's disease model in this work.
Aliases: Tg2576 mice, APP transgenic mice
REFERENCES
Showing 1-68 of 68 references · Page 1 of 1