Impaired spine stability underlies plaque-related spine loss in an Alzheimer's disease mouse model

Tara L. Spires-Jones, Melanie Meyer-Luehmann, Jennifer D. Osetek, Phillip B. Jones, Edward A. Stern, Brian J. Bacskai, Bradley T. Hyman

Research output: Contribution to journalArticlepeer-review

158 Scopus citations

Abstract

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 forma tion and elimination. To investigate effects of plaques on spine stability in vivo, we observed cortical neu rons using multiphoton microscopy in a mouse model of amyloid pathology before and after extensive plaque deposition. We also observed age-matched non- transgenic mice to study normal effects of aging on spine plasticity. We found that spine density and struc tural 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 con trol animals, spine formation and elimination were equivalent over 1 hour of observation (∼5% of observed spines), resulting in stable spine density. However, in aged Tg2576 mice spine elimination increased, specifi cally in the immediate vicinity of plaques. Spine forma tion was unchanged, resulting in spine loss. These data show a small population of rapidly changing spines in adult and even elderh/ mouse cortex; further, in the vicinity of amyloid plaques, spine stability is markedly impaired leading to loss of synaptic structural integrity.

Original languageEnglish
Pages (from-to)1304-1311
Number of pages8
JournalAmerican Journal of Pathology
Volume171
Issue number4
DOIs
StatePublished - Oct 2007
Externally publishedYes

Bibliographical note

Funding Information:
Supported by National Institutes of Health grants AG08487 and AG00277 , a John Douglas French Alzheimer's Foundation Fellowship, and Alzheimer's Association Pioneer Award and grant EB00768 .

Funding

Supported by National Institutes of Health grants AG08487 and AG00277 , a John Douglas French Alzheimer's Foundation Fellowship, and Alzheimer's Association Pioneer Award and grant EB00768 .

FundersFunder number
John Douglas French Alzheimer's Foundation
National Institutes of HealthAG00277, AG08487
Alzheimer's AssociationEB00768

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