Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy.
Accumulation of amyloid-beta (Abeta) 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 (approximately 50%) extends approximately 20 mum from plaque edges. Importantly, a robust decrement (approximately 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.
Spires
Tara L
TL
Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Meyer-Luehmann
Melanie
M
Stern
Edward A
EA
McLean
Pamela J
PJ
Skoch
Jesse
J
Nguyen
Paul T
PT
Bacskai
Brian J
BJ
Hyman
Bradley T
BT
D000544:Alzheimer Disease; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D003712:Dendrites / Q000648:ultrastructure; D049229:Dendritic Spines / Q000187:drug effects* / Q000648:ultrastructure*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins; D049408:Luminescent Agents; D051379:Mice; D008822:Mice, Transgenic; D008853:Microscopy; D009154:Mutation; D009434:Neural Pathways / Q000473:pathology; D016501:Neurites; D009474:Neurons / Q000648:ultrastructure; D017785:Photons; D058225:Plaque, Amyloid / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000494:pharmacology; D016708:Synaptophysin / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D049408:Luminescent Agents; D020033:Protein Isoforms; D016708:Synaptophysin; D049452:Green Fluorescent Proteins