Boston University Medical Campus
Pathology and Laboratory Medicine

Ivana Delalle. M.D., Ph.D

Associate Professor

Contact information

Email: idelalle@bu.edu
Tel. 617 414 7014

Education

• Pathology/Neuropathology residency/fellowship, Massachussets General Hospital, Harvard Medical School;
• M.D./ Ph.D, School of Medicine, University of Zagreb, Croatia

Research interests

I. miRNAs in schizophrenia and bipolar disorder: This project (funded by R21 NIH MH 86079-01) applies a novel approach towards the search for biological markers for bipolar disorder (BD) and schizophrenia (SCH). Recently, small non-coding RNA molecules (microRNAs, miRNAs) were shown to regulate the expression of human CNS genes involved in cell processes and functions negatively affected in neuropsychiatric disorders, such as synaptic development and maturation, learning and memory.  Exosomes are well-characterized category of secretory vesicles that have been recently shown to contain mRNA, including miRNA.  The interesting property of exosomes is that they are able to attach themselves to recipient cells and release their content including genetic regulatory material such as miRNAs.  Our preliminary data indicate that exosomes can be isolated from frozen postmortem brain tissue (see electron micrograph below).

To test the hypothesis that exosomal miRNA content reflects disease specific-aberrations, we compare exosomal miRNA content in PFCs (Brodmann area 9, BA 9) of patients with BD, SCH and controls to establish BD exosomal miRNA profile.  Exosomes are extracted from the frozen postmortem PFCs (BA 9) from the patients diagnosed with SCH, BD and matching controls obtained from Harvard Brain Tissue Resource Center (McLean 66 cohort).  To establish cell-type specific miRNA profile in BD we are collaborating with Advanced Tissue Research Center at Harvard NeuroDiscovery Center (Dr. Charles Vanderburg) to use laser capture microscopy (LCM) mapping of neurons and glia in brain regions participating in mood manifestations (BA9, BA24 and ventral striatum) in BD and control samples from McLean 66 cohort.  We want to test the hypothesis that major cell- categories in different but interacting brain regions display specifically altered miRNA profiles in BD in comparison to controls.  Upon LCM mapping, neuronal and glial miRNAs are obtained using an miRNA extraction kit designed for small amount of miRNA (Molecular Devices Corporation), followed by a sensitive amplification protocol for each of the examined areas.  miRNA profiles, both exosomal and cellular are established using liquid phase miRNA multiplex bead arrays (Luminex) and subjected to computational analysis.  These experiments aim to improve our understanding of the mechanisms by which the signaling may be altered in BD and SCH.  In addition, novel regulatory miRNAs may emerge as potential biological markers for BD and SCH.

II. Cytoskeleton and Alzheimer’s disease:  Cytoskeletal reorganization in neurodegenerative diseases results in degenerative as well as regenerative morphological changes: dystrophic neurites as well as new, sprouting neuronal processes with growth cones often coexist, even within the same neuron.  Actin and tubulin are two major cytoskeletal proteins indispensable for normal neurite development and regenerative responses to injury and neurodegenerative stimuli.  We have previously shown that actin capping protein beta2 subunit, Capzb2, binds tubulin and, in the presence of tau, affects microtubule polymerization necessary for neurite outgrowth and normal growth cone morphology. Accordingly, Capzb2 silencing in hippocampal neurons results in short, dystrophic neuronal processes, reminiscent of the neurites seen in diverse neurodegenerative diseases: we demonstrated recently area- specific dynamics in the levels of Capzb2 protein expression in the individuals diagnosed with Alzheimer’s Disease (AD) and Huntington’s Disease.  We have evidence for the statistically significant increase in the Capzb2 expression in the postmortem hippocampi at the mid-stage, Braak and Braak (BB) III-IV, non-familial AD in comparison to controls.  The dynamics of Capzb2 expression in progressive AD stages cannot be attributed to reactive astrocytosis.  Rather, the increased expression of Capzb2 in BB III-IV may reflect neuronal regenerative response during AD progression.  This work has been partially supported by PHS grant T32 AG00015-21.

Current Abstracts:

Patricia F. Kao, David A. Davis, Charles Vanderburg, and Ivana Delalle: Capzb2 is specifically increased in the hippocampi of patients diagnosed with mid-stage non-familial Alzheimer’s disease. XVIIth International Congress of Neuropathology, September 2010, Salzburg, Austria.

Patricia F. Kao, Charles Vanderburg, Ann McKee, Sudha Seshadri and Ivana Delalle: Tissue markers of brain reserve during Alzheimer’s disease progression. Society for Neuroscience Meeting, November 2010, San Diego, CA.

Selected Articles:

1. Athanasios Zovoilis,  Hope Y Agbemenyah,  Roberto C Agis-Balboa,  Roman M Stilling,  Dieter Edbauer,  Pooja Rao, Laurent Farinelli,  Ivana Delalle,  Andrea Schmitt,  Peter Falkai,  Sanaz Bahari-Javan,  Susanne Burkhardt,  Farahnaz Sananbenesi &  Andre Fischer : microRNA-34c is a novel target to treat dementias The EMBO Journal doi:10.1038/emboj.2011.327.
2. Kao PF, Davis DA, Banigan MG, Vanderburg CR, Seshadri S, and Delalle I: Modulators of cytoskeletal reorganization in CA1 hippocampal neurons show increased expression in patients at  mid-stage Alzheimer’s disease. PLoS One  2010 Oct 13;5(10):e13337.PMID: 20967212
3. Davis DA, Wilson MH, Giraud J, Xie Z, Tseng H-C, England C, Hersckovitz H, Tsai L-H, Delalle I: Capzb2 interacts with ß-tubulin to regulate growth cone morphology and neurite outgrowth. PLoS Biol 2009 Oct; 7(10):e1000208. Epub 2009 Oct 6. PMID: 19806181.
4. Vanderburg CR, Davis DA, Diamond RE, Kao PF,  Delalle I: Capzb2 protein expression in the brains of patients diagnosed with Alzheimer’s disease and Huntington’s disease.  Translational Neuroscience 2010; 1(1): 55-58. (DOI: 10.2478/v10134-010-0008-9)
5. Delalle I,  Pfleger CM, Buff E, Lueras P, Hariharan IK. Mutations in the Drosophila orthologs of the F-actin capping protein alpha and beta subunits cause actin accumulation and subsequent retinal degeneration. Genetics 2005; 171:1757-1765.
6. Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai L-H. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. The EMBO Journal 2007; 26/13:3169-79.
7. Kim D, Frank CL, Dobbin MM, Tsunemoto RK, Tu W, Peng PL, Guan JS, Lee BH, Moy LY, Giusti P, Broodie N, Mazitschek R, Delalle I, Haggarty SJ, Neve RL, Lu Y, Tsai L-H: Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron 2008; 60(5): 803-817.