Research Faculty

Address
630 West 168th Street
P&S 12-420D
New York, NY 10032



Phone: 212-342-0533
Fax: 212-342-9096

oa1@columbia.edu
Education and Training
1981 M.D., University of Pisa, School of Medicine.
1991 Ph.D., University of Verona.


Affiliations
Anatomy & Cell Biology
Integrated Program
MD-PhD Program
Neurobiology & Behavior
Pathobiology
Taub Institute
Ottavio Arancio, M.D., Ph.D.
Associate Professor of Pathology & Cell Biology
Research Summary

Research in my laboratory stems from my life-long commitment to studying mechanisms of synaptic plasticity. I am interested in the cellular and molecular mechanisms that underlie long-lasting changes of synaptic function in both normal, healthy brains and in the brains of those affected by neurological disorders, in particular Alzheimer's disease (AD). Research in my laboratory has focused on the mechanisms by which amyloid-β (Aβ) peptides interfere with both memory formation and the regulation of hippocampal long-term potentiation (LTP), an activity-dependent model of synaptic plasticity that is thought to be related with learning and memory. I am interested in how regulation of gene activation and silencing, post-translational mechanisms, channel opening, intracellular calcium transients and changes in transmitter release machinery might participate in basal synaptic transmission and in synaptic plasticity. The research of my laboratory is answering the following questions:

1) How does Aβ elevation impair synaptic plasticity and memory? Experiments addressing this question examine Aβ-induced modifications in epigenetic and post-translational mechanisms.

Epigenetic mechanisms: We are exploring steps affected at the downstream level of CREB phosphorylation. CREB plays an important role together with CBP in gene transcription through histone acetylation leading to the loss of chromosomal repression and transcription of genes needed for synthesis of proteins underlying memory formation. Thus, we are investigating if reduced histone acetylation follows the reduction of CREB phosphorylation by Aβ elevation. Chromatin changes do not have to be necessarily limited to histone acetylation. As a mechanism which can "lock in" particular states of pathological gene expression in human cells, DNA methylation is an obvious candidate for contributing to the inexorably progression and irreversibility of AD in the middle to late stages of the disease. Additionally, DNA methylation may act early in AD, as some very recent work has shown that the proper regulation of gene expression in memory formation is not only controlled by the transcriptional machinery but also modulated by epigenetics. We are currently identifying genes that are differentially methylated following Aβ elevation.

Post-translational mechanisms: SUMOylation is a post-translational mechanism other than phosphorylation involving the covalent attachment of a small 11 kDA protein moiety, SUMO (Small Ubiquitin-like MOdifier), to substrate proteins. We are investigating if SUMOylation plays a role in learning and memory. We are also investigating whether it is modified following Aβ elevation and if by re-establishing normal SUMOylation one can revert synaptic and cognitive dysfunctions in AD mouse models.

In addition, we are investigating the role of the serine/threonine phosphatase, PP2A, in sensitivity and resistance to oligomer-induced behavioral and physiological impairments. Elevated levels of homocysteine and impaired methyl-donor metabolism have been linked to increased Alzheimer’s disease (AD) risk in humans and increased AD-related pathology in cell and animal models. The serine/threonine phosphatase, PP2A, is regulated by site-specific methylation, and misregulated PP2A activity has been proposed to mediate the effects of impaired methyl-donor metabolism on AD. We generated transgenic mice that over express the PP2A methylesterase, PME-1 or the PP2A methyl transferase, LCMT-1, and found that PME-1 over expression enhanced, and LCMT-1 over expression reduced the physiological and behavioral impairments caused by acute oligomeric A exposure. These transgenes were without effect on A production or the response to physiological concentrations of A, suggesting that they selectively affect the response of neurons to pathological A levels. These data support a role for reduced PP2A methylation in increasing AD risk in hyperhomocysteinemic individuals and suggest potential therapeutic effects for increased PP2A methylation in AD treatment or prevention. We are currently investigating the involvement of PP2A in tau induced and traumatic brain injury.

Tau oligomer-induced synaptic and memory loss: tau is not only present inside cells. Tau can be found extracellularly. We have found that tau can oligomerize in the cerebro-spinal fluid. We have also found that that extracellular tau oligomers can induce synaptic and memory loss. We are currently defining the mechanisms of such effects.

2) Does Aβ play a critical positive role in synaptic plasticity and memory? Recent research performed in my laboratory has shown that low levels of Aβ similar to those present in the brains of healthy individuals throughout life, enhance LTP and memory. We are continuing these studies to explore the role of endogenous Aβ in LTP and memory. We are addressing the following questions: can we visualize release of endogenous Aβ and follow its fate in normal physiological conditions? Are changes in APP processing by the secretases or other changes in APP metabolism responsible for the increase in Aβ levels during synaptic activity? Does release of Aβ from intracellular pools account for the increase in Aβ following activity in the presynaptic terminal? Most importantly, a fundamental question originating from the discovery of a positive function for Aβ is: how does it happen that a molecule performing a positive function gains a new and negative function?

All this work would be incomplete without the goal to move each project forward to the stage where it not only provides new biological insights but also, when appropriate, serve as the basis for future development of new therapeutic strategies. Such translational research is enhanced by collaborations with medicinal-chemists, biotech specialists, pathologists and clinicians. These studies should lead to the design of novel therapeutic approaches that might be effective in preventing or delaying the onset of AD and other neurodegenerative diseases characterized by cognitive disorders.

Selected Publications

1. Teich AF, Patel M, Arancio O. A Reliable Way to Detect Endogenous Murine β-Amyloid. PLoS One. 2013; 8(2):e55647. PMID: 23383341.

2. Fiorito J, Saeed F, Zhang H, Staniszewski A, Feng Y, Francis YI, Rao S, Thakkar DM, Deng SX, Landry DW, Arancio O. Synthesis of quinoline derivatives: Discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer's disease. Eur J Med Chem. 2013; 60:285-94. PMID: 23313637.

3. Pozueta J, Lefort R, Ribe EM, Troy CM, Arancio O, Shelanski M. Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice. Nat Commun. 2013 Jun 10;4:1939. doi: 10.1038/ncomms2927. PMID: 23748737.

4. Orozco IJ, Koppensteiner P, Ninan I, Arancio O. The schizophrenia susceptibility gene DTNBP1 modulates AMPAR synaptic transmission and plasticity in the hippocampus of juvenile DBA/2J mice. Mol Cell Neurosci. 2013 Dec 6. doi:pii: S1044-7431(13)00117-6. 10.1016/j.mcn.2013.12.003. [Epub ahead of print]

5. Lee L, Kosuri P, Arancio O. Picomolar Amyloid-β Peptides Enhance Spontaneous Astrocyte Calcium Transients. J Alzheimers Dis. 2014 Jan 1;38(1):49-62. doi: 10.3233/JAD-130740. PMID: 23948929.

6. Qin Z, Luo J, Vandevrede L, Tavassoli E, Fa' M, Teich AF, Arancio O, Thatcher GR. Design and Synthesis of Neuroprotective Methylthiazoles and Modification as NO-Chimeras for Neurodegenerative Therapy. J Med Chem. 2012; 55:6784-801. PMID: 2779770.

7. Hashimoto G, Sakurai S., Teich AF, Saeed F, Aziz F, Arancio O. 5-HT4 receptor stimulation leads to soluble APPα production through MMP-9 up-regulation. J Alzheimers Dis. 2012; 32:437-45, PMID: 22810092.

8. Ren H, Orozco IJ, Su Y, Suyama S, Gutiérrez-Juárez R, Horvath TL, Wardlaw SL, Plum L, Arancio O, Accili D. FoxO1 Target Gpr17 Activates AgRP Neurons to Regulate Food Intake. Cell. 2012; 149:1314-26. PMID: 22682251.

9. Liu X, Betzenhauser MJ, Reiken S, Meli A, Xie W, Chen BX, Arancio O, Marks AR. Role of leaky neuronal ryanodine receptor in stress-induced cognitive dysfunction. Cell, 2012; 150:1055-67. PMID: 22939628.

11. Puzzo, D., Privitera, L., Fa’, M., Staniszewski, A., Hashimoto, G., Aziz, F., Sakurai, M., Ribe, E.M., Troy, C.M., Mercken, M., Jung, S.S., Palmeri, A., *Arancio, O. Endogenous amyloid-β is necessary for hippocampal synaptic plasticity and memory. Ann Neurol. 2011; 69:819-30. PMID: 21472769.

12. Tamayev R, Matsuda S, Giliberto L, Arancio O, D'Adamio L. APP heterozygosity averts memory deficit in knockin mice expressing the Danish dementia BRI2 mutant. EMBO J. 2011; 30:2501-9. PMID: 21587206.

13. Wu SH, Arevalo JC, Neubrand VE, Zhang H, Arancio O, Chao MV. The Ankyrin Repeat-rich Membrane Spanning (ARMS)/KIDINS220 scaffold protein is regulated by activity-dependent calpain proteolysis and modulates synaptic plasticity. J Biol Chem. 2010; Oct 13. [Epub ahead of print] PMID: 20943655.

14. Tamayev, R., Matsuda, S., Fa’, M., Arancio, O., D'Adamio, L. Danish dementia mice suggest that loss of function and not the amyloid cascade causes synaptic plasticity and memory deficits. Proc Natl Acad Sci U S A. 2010; 107:20822-7. PMID: 2109826874.

15. Smith DL, Pozueta J, Gong B, Arancio O, Shelanski M. Reversal of long-term dendritic spine alterations in Alzheimer disease models. Proc Natl Acad Sci U S A. 2009; 106:16877-82.

16. Francis, I.Y., Fà, M., Ashraf, H., Zhang, H., Staniszewski, A., Latchman, D.S., *Arancio, O. Dysregulation of histone acetylation in the APP/PS1 mouse model of Alzheimer's disease. J Alzheimers Dis. 2009 18: 131-9.

17. Puzzo, D., Staniszewski, A., Deng, S-X, Privitera, L., Leznik, E., Liu, S., Zhang, H., Feng., Y., Palmeri, A., Landry, D-W, Arancio, O. Phosphodiesterase 5 inhibition improves synaptic function, memory and Amyloid-beta load in an Alzheimer's Disease Mouse Model. J. Neurosci. 2009 29:8075-86.

18. Puzzo, D., Privitera, L., Leznik, E., Fa M., Staniszewski, A., Palmeri, A. Arancio, O. Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J. Neurosci. 2008 28:14537-45

19. Trinchese, F., Fa M., Liu, S., Zhang, H., Hidalgo, A., Schmidt, S., Yamaguchi, H., Yoshii, N., Mathews, P., Nixon, R., Arancio, O. Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease. J. Clin. Invest., 2008; 118: 2796-807.

20. Serulle, Y., Zhang, S, Ninan I., Puzzo, D., McCarthy, M., Khatri, L., Arancio, O. and Ziff, E.B. A novel GluR1-cGKII interaction regulates AMPA receptor trafficking. Neuron. 2007; 56: 670-88.

21. Ninan, I., Liu, S., Rabinowitz, D., Arancio, O. Early Presynaptic Changes during Plasticity in Cultured Hippocampal Neurons. EMBO J. 2006; 25: 4361-4371.

22. Gong, B., Cao, Z., Zheng, P., Vitolo, O.V., Liu, S., Staniszewski, A., Moolman, D., Zhang, H., Shelanski, M., Arancio, O. Ubiquitin Hydrolase Uch-L1 Rescues β-Amyloid-Induced Decreases in Synaptic Function and Contextual Memory. 2006; Cell 126: 775-788.

23. Yano, H., Ninan, I., Zhang, H., Milner, T.A., Arancio, O., Chao, M.V. BDNF-mediated neurotransmission relies upon a myosin VI motor complex. Nat. Neurosci. 2006; 9: 1009-18.

24. Gong, B., Vitolo, O.V., Trinchese, F., Liu, S., Shelanski, M., Arancio, O. Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model following rolipram treatment. J. Clin. Invest ., 2004; 114: 1624-1634.

25. Ninan, I., Arancio, O. Presynaptic CaMKII is necessary for synaptic plasticity in cultured hippocampal neurons. Neuron, 2004; 42: 129-141.

26. Liu, S., Ninan, I., Antonova, I., Battaglia, F., Trinchese, F., Narasanna, A., Kholodilov, N., Dauer, W., Hawkins, R.D., Arancio, O. α-synuclein produces a long-lasting increase in neurotransmitter release. EMBO J., 2004, 23: 4506-16.

Honors and Awards

1987
G. Moruzzi Fellowship, Fidia Research Foundation, Washington, D.C., USA

1990
Anna Villa Rusconi Foundation Prize, Varese, Italy
Fellowship, Fidia SPA, Abano Terme, Italy

1991
Fellowship, Fidia SPA, Abano Terme, Italy
INSERM Poste vert Fellowship, Paris, France

1994
Fellowship, University of Bologna, Bologna, Italy

1996
Chairperson, Society for Neuroscience, Washington, D.C., U.S.A.

2007
AHAF, Centennial Award
Alzheimer's Association, Zenith Award

2008
Margaret Cahn Research Award

2010
Edward N. and Della L. Thome Memorial Foundation, Award

Committees , Council, and Professional Society Memberships

Society for Neuroscience (USA)

I.B.R.O.

Italian Society for EEG and Clinical

Neurophysiology

Italian Society for Neuroscience

Italian Society for Physiology


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