Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo.
Aggregation of the amyloid-beta (Abeta) peptide in the extracellular space of the brain is central to Alzheimer's disease pathogenesis. Abeta aggregation is concentration dependent and brain region specific. Utilizing in vivo microdialysis concurrently with field potential recordings, we demonstrate that Abeta levels in the brain interstitial fluid are dynamically and directly influenced by synaptic activity on a timescale of minutes to hours. Using an acute brain slice model, we show that the rapid effects of synaptic activity on Abeta levels are primarily related to synaptic vesicle exocytosis. These results suggest that synaptic activity may modulate a neurodegenerative disease process, in this case by influencing Abeta metabolism and ultimately region-specific Abeta deposition. The findings also have important implications for treatment development.
Cirrito
John R
JR
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Yamada
Kelvin A
KA
Finn
Mary Beth
MB
Sloviter
Robert S
RS
Bales
Kelly R
KR
May
Patrick C
PC
Schoepp
Darryle D
DD
Paul
Steven M
SM
Mennerick
Steven
S
Holtzman
David M
DM
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D005089:Exocytosis / Q000502:physiology; D045604:Extracellular Fluid / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017551:Microdialysis; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D019580:Perforant Pathway / Q000502:physiology; D058225:Plaque, Amyloid / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism
D016229:Amyloid beta-Peptides