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John Cirrito, PhD

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.

Medical Training

Dr. Cirrito was raised in Ft. Lauderdale, FL where he attended St. Thomas Aquinas High School. He received a B.S. from Boston College in Psychology/Biopsychology in 1998. His undergraduate research was with Dr. Michael Numan (Department of Psychology) studying the brain regions responsible for inhibition of maternal behavior in naïve rats. After graduating, he worked in Research and Development at NEN Life Sciences (Boston, MA). In 1999 he started his graduate work at Washington University in the Neuroscience Program. He trained in the laboratory of David Holtzman while researching amyloid-β clearance mechanisms in animal models of Alzheimer's disease. He developed a novel microdialysis technique to study the dynamics of brain amyloid-β levels in living mice. In 2006 he won an award for outstanding technological leadership from Scientific American; the microdialysis technique was chosen as one of the top 50 scientific achievements of that year (SciAm 50 Award). In 2004, Dr. Cirrito received this Ph.D. and began a postdoctoral fellowship with Dr. Steven Mennerick in the Department of Psychology. There he studied the synaptic regulation of amyloid-β metabolism. He became a Research Instructor (2006) then Research Assistant Professor (2008). As faculty, he opened and became director of the In Vivo Microdialysis Core Facility (2007). The facility helps academic and corporate groups test or screen compounds for their ability to modulate amyloid-β metabolism in animal models. In 2010, Dr. Cirrito became Assistant Professor in the Department of Neurology and opened his own laboratory. He is a member of the Hope Center for Neurological Disorders and the Knight Alzheimer's Disease Research Center.

Selected 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.

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