Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer's disease

Melanie Meyer-Luehmann, Tara L. Spires-Jones, Claudia Prada, Monica Garcia-Alloza, Alix De Calignon, Anete Rozkalne, Jessica Koenigsknecht-Talboo, David M. Holtzman, Brian J. Bacskai, Bradley T. Hyman

Research output: Contribution to journalArticlepeer-review

799 Scopus citations

Abstract

Senile plaques accumulate over the course of decades in the brains of patients with Alzheimer's disease. A fundamental tenet of the amyloid hypothesis of Alzheimer's disease is that the deposition of amyloid-β precedes and induces the neuronal abnormalities that underlie dementia. This idea has been challenged, however, by the suggestion that alterations in axonal trafficking and morphological abnormalities precede and lead to senile plaques. The role of microglia in accelerating or retarding these processes has been uncertain. To investigate the temporal relation between plaque formation and the changes in local neuritic architecture, we used longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice. Here we show that plaques form extraordinarily quickly, over 24 h. Within 1-2 days of a new plaque's appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology.

Original languageEnglish
Pages (from-to)720-724
Number of pages5
JournalNature
Volume451
Issue number7179
DOIs
StatePublished - Feb 7 2008

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