John R. Cirrito, Ph.D.
Amyloid-beta (Abeta) peptide accumulation within the brain extracellular space, as toxic oligomers and plaques, is strongly believed to be the primary cause of Alzheimer`s disease (AD). My lab focuses on understanding the metabolism Abeta within the brain extracellular fluid, or interstitial fluid (ISF). We developed a novel in vivo microdialysis technique that enables us to specifically measure ISF Abeta within the brains of living and awake wildtype and APP transgenic mice. The technique permits hourly sampling of Abeta for several days, thus providing kinetic information about how Aβ levels change over time under various settings such as aging, behavior, drug treatment, and genetic manipulation. We recently discovered that synaptic activity is a critical regulator of Abeta production in the living brain; as synaptic activity increases ISF Abeta levels rapidly increase and vice versa as synaptic activity declines. This occurs following pharmacologic manipulation of synaptic activity as well as during physiological fluctuations in activity such as sleep/wake cycles or stress. Synaptic transmission causes more clathrin-mediated endocytosis within the presynaptic terminal as synaptic vesicle membrane recycles. As this occurs, APP is internalized into endosomes where Abeta is produced followed by secretion into the ISF. APP is found within the axonal compartment as well as the dendritic compartment. Postsynaptic signaling mechanisms, through a wide variety of receptors including NMDA, muscarinic acetylcholine, and serotonin receptors can modulate APP processing and alter Abeta levels as well. One aspect of our current research is focused on postsynaptic signaling mechanisms that decrease Abeta generation including identification of effectors on the cell surface and the signaling pathways within the neuron that impact Abeta production. Activation of the MAPK/ERK signaling pathway decreases Abeta levels in vivo. ERK can be activated by a multitude of extracellular ligands, including NMDA receptors and serotonin receptors. We can demonstrate the agents that increase serotonin signaling, such as SSRI antidepressants, decrease Aβ levels in the mouse brain which entirely depends on ERK signaling. Inhibiting ERK or MEK (another step in the ERK pathway) completely blocks the SSRI-dependent decrease in Abeta. Work by a collaborator at Washington University, Dr. Yvette Sheline, suggests that SSRI antidepressants reduce plaque load in humans as well. Our hope is that understanding the pathways that control Abeta levels will help us understand risk factors of AD as well as provide new therapeutic targets. My lab is also developing several new techniques, including in vivo synaptic plasticity assays to determine how various forms of Abeta impact synaptic transmission in a physiological setting. We are also developing new protein-specific electrochemical technologies to measure Abeta in the scale of seconds or milliseconds as opposed to hours currently available with our microdialysis technique. Such an approach would allow us to measure Abeta release from neurons in real-time and further define the complex relationship between synaptic activity and Abeta generation.
Cirrito JR, Disabato BM, Restivo JL, Verges DK, Goebel WD, Sathyan A, Hayreh D, D`Angelo G, Benzinger T, Yoon H, Kim J, Morris JC, Mintun MA, Sheline YI. Serotonin signaling is associated with lower amyloid-beta levels and plaques in transgenic mice and humans. Proc Natl Acad Sci U S A 2011 108:14968-14973. PMCID 21873225.
Verges DK, Restivo JL, Goebel WD, Holtzman DM, Cirrito JR. Opposing Synaptic Regulation of Amyloid-beta Metabolism by NMDA Receptors In Vivo. J Neurosci 2011 31:11328-11337. PMCID 21813692.
Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. Amyloid- beta Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle. Science 2009 326(5955):1005-7.
Yan P, Bero AW, Cirrito JR, Xiao Q, Hu X, Wang Y, Gonzales E, Holtzman DM, Lee JM. Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice. Journal of Neuroscience 2009 29: 10706-10714.
Han BH, Zhou ML, Abousaleh F, Brendza RP, Dietrich HH, Koenigsknecht-Talboo J, Cirrito JR, Milner E, Holtzman DM, Zipfel GJ. Cerebrovascular dysfunction in amyloid precursor protein transgenic mice: contribution of soluble and insoluble amyloid-beta peptide, partial restoration via gamma-secretase inhibition. Journal of Neuroscience 2008 28: 13542-13550.
Cirrito JR, Kang JE, Lee J, Stewart FR, Verges DV, LM Silverio, Bu G, Mennerick S, Holtzman DM. Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron 2008 58:42-51.
Cirrito JR, Stewart FR, Mennerick S, Holtzman DM. Synaptic Transmission Dynamically Modulates Interstitial Fluid Amyloid-beta Levels. Synaptic Plasticity and the Mechanisms of Alzheimer’s Disease Selkoe, Christen, Springer 2008 133-144.
Last Updated: 8/9/2012 4:09:36 PM
Model of presynaptic Abeta generation