John Cirrito, PhD

Associate Professor of Neurology

Phone314-362-1610

Fax314-362-2244

Emailcirritoj@neuro.wustl.edu

Related Links

Publications

  • Cirrito JR, May PC, O’Dell MA, Taylor JW, Parsadanian M, Cramer JW, Audia JE, Nissen JS, Bales KR, Paul SM, DeMattos RB, Holtzman DM ( 2003). In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid- metabolism and half-life. J Neuroscience, 23(26).
  • DeMattos RB*, Cirrito JR*, Parsadanian M, May PC, O’Dell MA, Taylor JW, Harmony JA, Aronow BJ, Bales KR, Paul SM, Holtzman DM (2004). ApoE and Clusterin Cooperatively Suppress A Levels and Deposition. Evidence that ApoE Regulates Extracellular A Metabolism In Vivo. Neuron 41:193-202. * Co-first authors
  • Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn MB, Jiang H, Prior JL, Sagare A, Bales KR, Paul SM, Zlokovic BV, Piwnica-Worms D, Holtzman DM (2005). P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clinical Investigation 115(11):3285-3290.
  • Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM (2005). Synaptic Activity Regulates Interstitial Fluid Amyloid-beta Levels In Vivo. Neuron 48(6):913-922.
  • Cirrito JR, Stewart FR, Mennerick S, Holtzman DM (2008). Synaptic Transmission Dynamically Modulates Interstitial Fluid Amyloid-beta Levels. Synaptic Plasticity and the Mechanisms of Alzheimer’s Disease. Selkoe, Christen, Springer: 133-144.
  • Cirrito JR, Kang JE, Lee J, Stewart FR, ¬¬Verges DV, LM Silverio, Bu G, Mennerick S, Holtzman DM (2008). Endocytosis is required for synaptic activity-dependent release of amyloid- in vivo. Neuron, 58:42-51.
  • Cao C, Cirrito JR, Lin X, Wang L, Verges DK, Dickson A, Mamcarz M, Zhang C, Mori T, Arendash GW, Holtzman DM, Potter H (2009). Caffeine Suppresses Amyloid-beta Levels in Plasma and Brain of Alzheimer’s Disease Transgenic Mice. Journal of Alzheimers Disease, 17:681-697.
  • Yan P, Bero AW, Cirrito JR, Xiao Q, Hu X, Wang Y, Gonzales E, Holtzman DM, Lee JM (2009). Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice. Journal of Neuroscience, 29:10706-10714.
  • Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM (2009). Amyloid- β Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle (2009). Science. 326(5955):1005-7.
  • Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee JM, Holtzman DM (2011). Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nature Neuroscience, 14(6):750-6.
  • Verges DK, Restivo JL, Goebel WD, Holtzman DM, Cirrito JR (2011). Opposing Synaptic Regulation of Amyloid-β metabolism by NMDA Receptors In Vivo. J Neuroscience, 31(31):11328-37.
  • Cirrito JR, Disabato B, Restivo JL, Verges DK, Goebel WG, Sathyan A, Hayreh D, D’Angelo G, Benzinger T, Yoon H, Kim J, Morris JC, Mintun MA, and Sheline YI (2011). Serotonin signaling and amyloid-β metabolism: a translational study in transgenic mice and humans. Proceedings of the National Academy of Sciences, In press.

Amyloid-β (Aβ) 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 group’s research has focused on understanding the metabolism of Aβ within the brain extracellular fluid, or interstitial fluid (ISF). We developed an in vivo microdialysis technique that enables us to specifically measure ISF Aβ within the brains of living and awake wildtype and APP transgenic mice. The technique permits hourly sampling of Aβ 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 discovered that synaptic activity was a critical regulator of Aβ production in the living brain; as synaptic activity increases ISF Aβ 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 Aβ is produced followed by secretion into the ISF. Data in humans is consistent with brain regions that exhibit the highest neuronal activity are the most vulnerable to developing AD pathologies such as Aβ plaques.

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 Aβ levels. One aspect of our current research is focused on postsynaptic signaling mechanisms that decrease Aβ generation including identification of effectors on the cell surface and the signaling pathways within the neuron that impact Aβ production. Activation of the MAPK/ERK signaling pathway decreases Aβ 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 vivo which entirely depends on ERK. Chronic treatment with SSRIs reduces plaque load in AD mouse models. Work by a collaborator at Washington University, Dr. Yvette Sheline, suggests that serotonin signaling induced by SSRI antidepressants is associated to less plaque load in humans as well. Our hope is that understanding the pathways that control Aβ levels will help us understand risk factors of AD as well as provide new therapeutic targets.