Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo.

By John R. Cirrito, Kelvin A. Yamada, M. Finn, R. S. Sloviter, K. Bales, P. May, D. Schoepp, S. Paul, S. Mennerick, D. Holtzman. Neuron, 2005

1,291 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/e02feeb59dca9a8218ae02e9f67256bcfc6a7325

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Citations in the corpus

The role of microglia in amyloid clearance from the AD brain (2010, neutral): “Ab is secreted from neurons as a consequence of normal synaptic transmis- sion (Cirrito et al. 2005; Kamenetz et al. 2003).”
Cortical Hubs Revealed by Intrinsic Functional Connectivity: Mapping, Assessment of Stability, and Relation to Alzheimer’s Disease (2009, neutral): “Using a transgenic mouse model, Holtzman, Cirrito, and colleagues demonstrated that neuronal stimulation increases the abundance of A in the extracellular space (Cirrito et al., 2005) and further that synaptic transmission increases APP endocytosis, providing a candidate mechanism for the observed i”
Unrest at rest: Default activity and spontaneous network correlations (2007, neutral): “A speculative possibility is that lifelong default network activity patterns may augment an activity- or metabolism-dependent cascade that leads to the formation of Alzheimer pathology and the eventual symptoms of the disease (Buckner et al., 2005; see also Cirrito et al., 2005; Selkoe, 2006).”
Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. (2008, positive): “This is in agreement with previous studies that have implicated AsISF in disease pathogenesis ( Cirrito et al., 2005; DeMattos et al., 2004).”
Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. (2012, background): “This neuronal activity-dependent regulation of Ab secretion has been observed during pathological events, such as epileptiform activity induced by electrical stimulation (Cirrito et al. 2005), as well as during normal physiological processes, such as the sleep–wake cycle (Kang et al.”
Picomolar amyloid-β positively modulates synaptic plasticity and memory in hippocampus (2008, neutral): “Because activation of 7-nAChRs is necessary for the A -induced increase of synaptic plasticity and memory, we propose a model whereby A released by neuronal activity during vesicle exocytosis (Cirrito et al., 2005) under normal conditions may modify glutamate release with a mechanism dependent upon ”
Amyloid-β Induced Neuronal Dysfunction in Alzheimer’s Disease: From Synapses toward Neural Networks (2010, background): “Subsequent studies provided evidence that neuronal activity regulates Aβ productio”
Linking Lipids to Alzheimer’s Disease: Cholesterol and Beyond (2011, background): “Synapses are particularly affected, not only because they are major sites of amyloid-β release but also because amyloid-β release itself is enhanced by synaptic activit”
Activity Dependent Degeneration Explains Hub Vulnerability in Alzheimer's Disease (2012, background): “In addition to the presumed role of disinhibition mentioned in the previous paragraph, a prominent role of excessive neuronal activity in AD pathogenesis has been suggested before: several studies have demonstrated a direct link between neuronal activity and the development of amyloid plaques in tra”