Efrat Levy, Ph.D.

Associate Professor
Departments of Psychiatry and Pharmacology
New York University School of Medicine

Research Scientist
The Center for Dementia Research
Nathan S. Kline Institute
140 Old Orangeburg Road
Orangeburg, NY 10962
(845)398-5540
elevy@nki.rfmh.org
The Levy Lab
NYU Profile

Education

  • M.Sc. (with distinction) The Hebrew University, Israel (Endocrinology)
  • Ph.D. The Hebrew University, Israel (Cell Biology)

Postdoctoral Training

  • Molecular Biology, Department of Biochemistry, New York University School of Medicine
  • Molecular Pathology, Department of Pathology, New York University School of Medicine

Research Interests

Cystatin C: A Potential Target for Treatment of Neurodegenerative Disorders in General and Alzheimer's Disease in Particular

Cerebral amyloidosis comprises a heterogeneous group of conformational disorders of different etiologies characterized by the deposition of fibrillar proteins in the brain parenchyma and blood vessel walls. The focus of my research has been the elucidation of common features of amyloid deposition diseases:

  • Characterizing the regulation of processing of amyloid precursor proteins
  • Defining processes involved in the conversion of soluble protein to the insoluble, fibrillar form
  • Identifying factors that target ubiquitously expressed proteins for deposition at restricted locations within particular tissues

Two different amyloid proteins have been extensively studied in our laboratory: amyloid β (Aβ), the major constituent of the amyloid plaques in the brains of Alzheimer's disease patients and cystatin C deposited in cerebral vasculature of patients with hereditary cerebral hemorrhage with amyloidosis, Icelandic type. We have been studying factors that affect the production of amyloid proteins or their tendency to change their conformation and aggregate. We have recently shown that while a variant form of cystatin C is amyloidogenic, the wild type protein binds soluble Aβ and inhibits Aβ oligomerization and amyloidogenesis, protecting the brain against amyloid-induced toxicity. Moreover, we have been studying the physiological role of cystatin C in the repair of the nervous system. In vitro and in vivo studies propose that cystatin C directly protects neuronal cells as well as cerebral smooth muscle cells from a variety of toxic insults, including against the neurotoxicity induced by nutrition deprivation, oxidative stress, and oligomeric or fibrillar forms of Aβ. Our studies suggest two pathways of protection, involving induction of autophagy and induction of proliferation.
 

Studies are underway to identify peptide sequences within cystatin C protein that have anti-Aβ-aggregating activities. These short peptide sequences can serve as templates for drug design of cystatin C peptidomimetic compounds that will have enhanced anti-Aβ aggregation and/or neuroprotective properties. Compounds that have the ability to prevent the aggregation of Aβ or that enhance neuronal survival are likely efficacious in inducing disease modification by either delaying the onset of Alzheimer’s disease or by arresting and/or slowing disease progression. Furthermore, identification of cystatin C sequences with neuroprotective properties would provide significant beneficial effects for other neurodegenerative disorders.

Significant Publications
  1. Levy E, Lopez-Otin C, Ghiso J, Geltner D, Frangione B.  Stroke in Icelandic patients with hereditary amyloid angiopathy is related to a mutation in the cystatin C gene, an inhibitor of cysteine proteases. J Exp Med 1989;169:1771-1778.
  1. Levy E, Carman MD, Fernandez-Madrid I, Lieberburg I, Power MD, van Duinen SG, Bots GThAM, Luyendijk W, Frangione B.  Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 1990;248:1124-1126.
  1. Wei L, Walker LC, Levy E.  Cystatin C: Icelandic-like mutation in an animal model of cerebrovascular β-amyloidosis. Stroke 1996;27:2080-2085.
  1. Borg J-P, Ooi J, Levy E, Margolis B.  The PI domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein. Mol Cel Biol 1996;16:6229-6241.
  1. Wei L, Berman Y, Castaño EM, Cadene M, Beavis RC, Devi L, Levy E.  Instability of the amyloidogenic cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type. J Biol Chem 1998;273:11806-11814.
  1. Sastre M, Turner RS, Levy E.  X11 interaction with β-amyloid precursor protein modulates its cellular stabilization and reduces amyloid β-protein secretion. J Biol Chem 1998;273:22351-22357.
  1. Levy E, Sastre M, Turner RS.  X11 modulation of β-amyloid precursor protein cellular stabilization and reduction of amyloid β-protein secretion. In: Iqbal K, Swaab DF, Winblad B, Wisniewski HM, eds, Alzheimer's disease and related disorders. Chichester, England: John Wiley and Sons, 1999;397-404.
  1. Levy E, Sastre M, Kumar A, Gallo G, Piccardo MD, Ghetti B, Tagliavini F.  Codeposition of cystatin C with amyloid-β protein in the brain of Alzheimer's disease patients. J Neuropath Exp Neur 2001;60:94-104.
  1. Calero M, Pawlik M, Soto C, Castaño EM, Sigurdsson E, Kumar A, Gallo G, Frangione B, Levy E.  Distinct properties of wild-type and the amyloidogenic human cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type. J Neurochem 2001;77:628-637.
  1. Choi SI, Vidal R, Frangione B, Levy E.  Axonal transport of British and Danish amyloid peptides via secretory vesicles. The FASEB J express (published on line December 4, 2003) 2004;18:373-375.
  1. Pawlik M, Sastre M, Calero M, Mathews PM, Schmidt SD, Nixon RA, Levy E.  Overexpression of human cystatin C in transgenic mice does not affect levels of endogenous brain amyloid β peptide. J Mol Neurosc 2004;22:13-18.
  1. Sastre M, Calero M, Pawlik M, Mathews PM, Kumar A, Danilov V, Schmidt SD, Nixon RA, Frangione B, Levy E.  Binding of cystatin C to Alzheimer’s amyloid β inhibits amyloid fibril formation. Neurobiol Aging 2004;25:1033-1043.
  1. Jung S, Levy E.  Murine cerebrovascular cells as a cell culture model for cerebral amyloid angiopathy. Isolation of smooth muscle and endothelial cells from mouse brain. In: Sigurdsson EM, ed,  Methods in Molecular Biology, vol. 299: Amyloid Proteins: Methods and Protocols. Totowa, NJ: Humana Press Inc., 2005;211-220.
  1. Prelli F, Pawlik M, Frangione B, Levy E.  Purification of human wild type or variant cystatin C from conditioned media of transfected cells.  In: Sigurdsson EM, ed,  Methods in Molecular Biology, vol. 299: Amyloid Proteins: Methods and Protocols. Totowa, NJ: Humana Press Inc., 2005;221-226.
  1. Tizon B, Levy E.  Protease inhibitors and their involvement in neurological disorders.  In: Lajtha A, ed,  Handbook of Neurochemistry and Molecular Neurobiology, 3rd Edition, vol. 7 New York, NY: Springer Publishers, 2006.
  1. Levy E, Prelli F, Frangione B.  Studies on the first described Alzheimer's disease amyloid β mutant, the Dutch variant. J Alzheimers Dis. 2006;9(3 Suppl):329-39.
  1. Levy E, Jaskolski M, Grubb A.  The role of cystatin C in cerebral amyloid angiopathy and stroke: cell biology and animal models. Brain Pathology 2006;16:60-70.
  1. Kaeser SA, Herzig MC, Coomaraswamy J, Kilger JE, Selenica M-LB, Winkler DT, Staufenbiel M, Levy E, Grubb A, Jucker M.  Cystatin C modulates cerebral β-amyloidosis. Nature Gen 2007;30(12):1437-1439.
  1. Mi W, Pawlik M, Sastre M, Jung SS, Radvinsky D, Klein AM, Sommer J, Schmidt SD, Nixon RA, Mathews PM, Levy E. Cystatin C inhibits amyloid β deposition in Alzheimer’s disease mouse models. Nature Gen 2007;30(12):1440-1442.
  1. Levy E.  Cystatin C: a potential target for Alzheimer’s treatment. Expert Review of Neurotherapeutics. 2008;8(5):687-689.