Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease.
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-beta 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.
Meyer-Luehmann
Melanie
M
Alzheimer's Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Spires-Jones
Tara L
TL
Prada
Claudia
C
Garcia-Alloza
Monica
M
de Calignon
Alix
A
Rozkalne
Anete
A
Koenigsknecht-Talboo
Jessica
J
Holtzman
David M
DM
Bacskai
Brian J
BJ
Hyman
Bradley T
BT
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001369:Axons / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors
D016229:Amyloid beta-Peptides