Impaired spine stability underlies plaque-related spine loss in an Alzheimer's disease mouse model.
Dendritic spines, the site of most excitatory synapses in the brain, are lost in Alzheimer's disease and in related mouse models, undoubtedly contributing to cognitive dysfunction. We hypothesized that spine loss results from plaque-associated alterations of spine stability, causing an imbalance in spine formation and elimination. To investigate effects of plaques on spine stability in vivo, we observed cortical neurons using multiphoton microscopy in a mouse model of amyloid pathology before and after extensive plaque deposition. We also observed age-matched nontransgenic mice to study normal effects of aging on spine plasticity. We found that spine density and structural plasticity are maintained during normal aging. Tg2576 mice had normal spine density and plasticity before plaques appeared, but after amyloid pathology is established, severe disruptions were observed. In control animals, spine formation and elimination were equivalent over 1 hour of observation ( approximately 5% of observed spines), resulting in stable spine density. However, in aged Tg2576 mice spine elimination increased, specifically in the immediate vicinity of plaques. Spine formation was unchanged, resulting in spine loss. These data show a small population of rapidly changing spines in adult and even elderly mouse cortex; further, in the vicinity of amyloid plaques, spine stability is markedly impaired leading to loss of synaptic structural integrity.
Spires-Jones
Tara L
TL
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital/ Harvard Medical School, Charlestown, Massachusetts, USA.
Meyer-Luehmann
Melanie
M
Osetek
Jennifer D
JD
Jones
Phillip B
PB
Stern
Edward A
EA
Bacskai
Brian J
BJ
Hyman
Bradley T
BT
D000544:Alzheimer Disease / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology*; D049229:Dendritic Spines / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology; D058225:Plaque, Amyloid / Q000473:pathology*
D016564:Amyloid beta-Protein Precursor
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