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Division of Neuropathology


Email ceberha@jhmi.edu
Phone (410) 502-5185

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Opthalmic Pathology


Charles G. Eberhart, M.D., Ph.D.

Director, Division of Neuropathology; Primary Appointment in Pathology
Member, Graduate Program in Pathobiology


My research focuses on the pathology and genetics of brain and eye tumors. We have studied the role played by the Wnt, Notch and Hedgehog pathways in medulloblastoma and other embryonal tumors, as well as malignant gliomas and ocular melanoma. These pathways regulate stem cell identity, and we have shown that Notch and Hedgehog are required in stem-like malignant glioma and medulloblastoma cells (“cancer stem cells”) as well. Our demonstration that pharmacological inhibition of either Notch or Hedgehog activity depletes stem-like cells from brain tumor cultures and slows or prevents clonogenic growth and xenograft initiation has helped to provide a rational for trials of Notch and Hedgehog inhibitors currently underway in children and adults. We also work on the pathobiology of low grade gliomas in the brain.

Publications
Bar EE, Chaudhry A, Lin A, Fan X, Schreck K, Matsui W, Piccirillo S, Vescovi AL, DiMeco F, Olivi A, Eberhart CG. Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 2007;25(10):2524-2533.

Fan X, Khaki L, Zhu TS, Soules ME, Talsma CE, Gul N, Koh C, Zhang J, Li YM, Maciazczyk J, Nikkhah G, Dimeco F, Piccirillo S, Vescovi AL, Eberhart CG. Notch pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells 2010;28:5-16.

Bar EE, Lin A, Mahairaki V, Matsui W, and Eberhart CG. Hypoxia Increases the Expression of Stem-Cell Markers and Promotes Clonogenicity in Glioblastoma Neurospheres. Am J Pathol 2010;177(3):1491-502.

Schreck KC, Taylor P, Marchionni L, Gopalakrishnan V, Bar EE, Gaiano N, Eberhart CG. The notch target hes1 directly modulates gli1 expression and hedgehog signaling: a potential mechanism of therapeutic resistance. Clin Cancer Res 2010:16(24):6060-70

Pierfelice TJ, Schreck KC, Dang L, Asnaghi L, Gaiano N, Eberhart CG. Notch3 Activation Promotes Invasive Glioma Formation in a Tissue Site-Specific Manner. Cancer Res 2011; 71;1115-25.101. PMCID: PMC3076023

Raabe EH, Lim KS, Kim JM, Meeker A, Mao XG, Nikkhah G, Maciaczyk J, Kahlert U, Jain D, Bar E, Cohen KJ, Eberhart CG. BRAF Activation Induces Transformation and Then Senescence in Human Neural Stem Cells: A Pilocytic Astrocytoma Model. Clin Cancer Res. 2011 Jun 1;17(11):3590-9.




Email pburger@jhmi.edu
Phone (410) 955-8378
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Peter C. Burger, M.D.

Primary Appointment in Pathology; Secondary Appointments in Neurosurgery, Oncology


My principal interest is in surgical neuropathology of both neoplastic and non-neoplastic diseases. For both, I am seeking the best methods by which these lesions can be diagnosed, and their biological behavior projected. Our current work explores molecular basis of gliomas, specifically molecular or cytogenetic abnormalities that correlate with tumor type and prognosis. We are involved in a multi-institutional study of the pathological cytogenetic, and molecular features of gliomas, particularly those that can be used to distinguish oligodendrogliomas from histologically similar lesions such as astrocytoma. We are also categorizing the cytogenetic and molecular features of pediatric astrocytomas and to subdivide medulloblastomas on the basis of their cytogenetic and molecular anatomy. With joint appointments in Oncology and Neurosurgery, I work closely with these disciplines in the evaluation of new therapies for CNS tumors. We have an active consult service for the interpretation of surgical specimens for brain and spinal cord tumors and other lesions.

Publications
Burger, P.C., Minn, A.Y., Smith, J.S., Borell, T.J., Jedlicka, A.E., Huntley,B.K., Goldthwaite, P.T., Jenkins, R.B., and Feuerstein, B.G.: Losses of Chromosomal Arms 1p and 19q in the Diagnosis of Oligodendroglioma. A Study of Paraffin-Embedded Sections. Modern Pathology 14:842-853, 2001.

Burger, P.C., Pearl, D.K., Aldape, K., Yates, A.J., Scheithauer, B.W.,Passe, S.M., Jenkins, R.B., and James, C.D. Small Cell Architecture - Ahistological Equivalent of EGFR Amplification in Glioblastoma Multiforme? J.Neuropathol. Exp. Neurol. 60:1099-1104, 2001.

Eberhart, C.G., Kratz, J.E., Schuster, A., Goldthwaite, P., Cohen, K.J.,Perlman, E.J., and Burger, P.C.: Comparative Genomic Hybridization Detects an Increased Number of Chromosomal Alterations in Large Cell/Anaplastic Medulloblastomas. Brain Pathology 121:36-44, 2001.

Eberhart, C.G., Kepner, J.L., Goldthwaite, P.T., Kun, L.E., Duffner, P.K.,Friedman, H.S., Strother, D.R., and Burger, P.C.: Histopathologic Grading of Medulloblastomas: A Pediatric Oncology Group Study. Cancer 94:552-560,2002.




Email lchen99@jhu.edu
Phone (410) 955-8102
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Liam L. Chen, M.D., Ph.D.

Primary Appointment in Pathology


My research interests focus on understanding the pathogenesis of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. We use Drosophila, fruit fly, as a model to study the mechanisms underlying central nervous system malfunction in humans. We express pathological human genes in the fly to generate an abnormal phenotype, such as age-dependent learning and memory defect, slowed motor activity, neuronal or glial cell loss. This phenotype can then be used in conjunction with the rich genetic toolbox that Drosophila researchers have developed to identify pathways that contribute to this degeneration. Their small size, rapid generation time, and low costs for maintenance make fruit flies ideal for studying neurodegenerative disease. The Drosophila models provide a platform for genome-wide screens and unbiased genetic screens to identify components of pathological pathways.

Publications
Chen L, Periquet M, Wang X, Negro A, McLean PJ, Hyman BT, Feany MB. Tyrosine and serine phosphorylation of alpha-synuclein have opposing effects on neurotoxicity and soluble oligomer formation. J Clin Invest. 2009. 119(11):3257-65.

Nosho K, Shima K, Irahara N, Kure S, Firestein R, Baba Y, Toyoda S, Chen L, Hazra A, Giovannucci EL, Fuchs CS, Ogino S. SIRT1 histone deacetylase expression is associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer. Mod Pathol. 2009. 22(7):922-32.

Chen L, Feany MB. Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci. 2005. 8(5):657-63.

Chen L, O'Keefe SL, Hodgetts RB. Control of Dopa decarboxylase gene expression by the Broad-Complex during metamorphosis in Drosophila. Mech Dev. 2002. 119(2):145-56.




Email koliat@jhmi.edu
Phone (410) 502-5172
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Vassilis E. Koliatsos, M.D.

Primary Appointment in Pathology; Secondary Appointments in Neurology, Neuroscience, Psychiatry
Member, Graduate Program in Neuroscience; Member, Graduate Program in Pathobiology


My main interest is mechanisms of traumatic and degenerative brain injury and repair. I have taken a pathophysiological approach to these problems, i.e. viewing pathology as an inappropriate – misplaced or excessive – version of a physiological process. For example, programmed cell death is a pivotal developmental mechanism for organism and organ formation, but excessive cell death signaling can cause neurodegenerative diseases such as Alzheimer’s disease (AD) and Amyotrophic Lateral Sclerosis (ALS). In a series of papers in the early and mid-90s, work in the lab characterized a number of neurotrophic peptides for key populations of neurons in the brain and spinal cord. We also demonstrated the role of programmed cell death in an index neurodegenerative disorder, i.e. Huntington’s disease.

I have recently turned my attention to cellular therapies for degenerative and traumatic diseases of the nervous system, i.e. applications involving embryonic and neural stem cells. We have worked on several lines of neural stem cells and have recently published pivotal studies showing efficacy of stem cell grafts in animal models of ALS. Although a lot of my previous work has focused on the more accessible peripheral motor system, I am now working to apply some of the lessons from this research to neocortical and limbic circuits implicated in memory and complex behaviors. To this effect, I have begun to characterize the role of small GABAergic cortical interneurons that serve as sensors of injury and may be actively engaged in both scavenging injured pyramidal neurons and laying the groundwork for ongoing cueing of neurons that emerge from existing neurogenic niches of the adult brain.

Publications
Yan J, Welsh AM, Xu L, Johe K and Koliatsos VE: Large-scale survival, differentiation and structural integration of human neural stem cells grafted into the adult rat spinal cord. PLoS Medicine 4(2), 2007: e39 doi:10.1371/journal.pmed.0040039

Yan J, Xu L, Welsh AM, Chen D, Hazel T, Johe K, and Koliatsos VE: Combined Immunosuppressive Agents or CD4 Antibodies Prolong Survival of Human Neural Stem Cell Grafts and Improve Disease Outcomes in Amyotrophic Lateral Sclerosis Transgenic Mice. Stem Cells 24:1976-1985, 2006.

Xu L, Yan J, Chen D, Welsh AM, Hazel T, Johe K, Hatfield G, and Koliatsos VE: Human Neural Stem Cell Grafts Ameliorate Motor Neuron Disease in SOD-1 Transgenic Rats. Transplantation 82:865-875, 2006.

Nasonkin IO, Koliatsos VE: Nonhuman sialic acid Neu5Gc is very low in human embryonic stem cell-derived neural precursors differentiated with B27/N2 and noggin: Implications for transplantation. Exp. Neurology 201:525-529, 2006.

Koliatsos,VE, Kecojevic,A, Troncoso,JC, Gastard,MC, Bennett,DA, Schneider,JA: Early involvement of small inhibitory cortical interneurons in Alzheimer's disease. Acta Neuropathologica 112:147-162, 2006.

Zhou Y, Zhou L, Chen H and Koliatsos VE: An AMPA glutamatergic receptor activation-nitric oxide synthesis step signals transsynaptic apoptosis in limbic cortex. Neuropharmacology 51(1):67-76, 2006.

Koliatsos VE, Dawson TM, Kecojevic A, Zhou Y, Wang Y-F, and Huang K-X: Cortical interneurons become activated by deafferentation and instruct the apoptosis of pyramidal neurons. PNAS 101:14264-14269, 2004.




Email tli1@jhmi.edu
Phone (410) 502-5174
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Tong Li, Ph.D.

Primary Appointment in Pathology


My research is focused on understanding the molecular mechanisms of neurodegenerative disorders, such as Alzheimer’s Disease (AD). My general approach is to create and characterize transgenic and knockout mouse models to study disease mechanisms and test therapeutic strategies for human diseases.

AD is characterized pathologically by neuritic amyloid plaques and neurofibrillary tangles (NFT) in the brain. Genetic and pathophysiological studies indicate that abnormal accumulation of Aß peptides, which is generated by sequential cleavage of APP by BACE1 and γ-secretase, plays a key role in AD. We have been focusing on understanding the function of γ-secretase in AD and other diseases. By generating and characterizing mice deleted for nicastrin, Aph-1a and Aph-1c (components of γ-secretase), we have demonstrated that these proteins are essential for γ-secretase activity. In addition, we found that partial reduction of γ-secretase activity significantly decreased the Aß amyloid burden in mice, suggesting that γ-secretase can serve as a therapeutic target for AD. Currently, we are testing the efficacy of targeting γ-secretase using γ-secretase inhibitors and modulators, and the combination approach that target both BACE1 and γ-secretase for AD therapy.

Interestingly, we also found that Nct+/- mice and Nct+/-;PS1+/- mice develop skin tumors mainly around the head and neck area, which histopathologically resemble human head and neck squamous cell carcinoma (HNSCC). These observations led us to hypothesize that γ-secretase can serve as a tumor suppressor and mice with mutation in genes encoding γ-secretase may serve as useful models for the study of human HNSCC. In supporting this view, in a recent phase III clinical trial, individuals who took a γ-secretase inhibitor (Semagacestat, Eli Lilly) for a prolonged period of time developed skin tumors that resemble those observed in our mouse models, which highlighted the importance of using animal models for preclinical studies of new therapies for human diseases. Our further study will also provide a better understanding of the mechanisms whereby γ-secretase functions as a tumor suppressor, information that will provide insight into the development of new therapeutics for the treatment of AD and its related skin cancer.

Abnormal protein aggregation is a common pathologically feature of neurodegenerative disease. We are interested in understanding the pathological functions of protein aggregations in AD, such as neuritic plaques and NFT. NFT is consisted of hyperphosphorylated tau protein, which is observed not only in AD but also in other neurodegenerative diseases, such as FTD and TBI related dementia. The relationship between Aß and tau pathologies during AD progression remains unclear. Recently, we have generated a mutant tau transgenic mouse line, in which four-repeat domain of human tau carrying the mutation ΔK280 (Tau4R-ΔK280) was conditionally expressed. By crossbreeding Tau4R-ΔK280 mice with a model of Aß amyloidosis, APPswe;PS1ΔE9 mice, we generated mice that develop both Aβ and Tau pathologies. Using this model, we will further evaluate the relationship between these two lesions and mechanism-based therapies targeting both Aß and tau. This new tau transgenic mouse model will also be used in studying the mechanisms and biomarkers of TBI related dementia.

Publications

Li T, Ma G, Cai H, Price DL, Wong PC. Nicastrin is required for assembly of presenilin/γ-secretase complexes to mediate Notch signaling and for processing and trafficking of β-amyloid precursor protein in mammals. J. Neuroscience. 23(8):3272-7, 2003

Li T, Wen H, Brayton C, Laird FM, Ma G, Peng S, Placanica L, Wu TC, Crain BJ, Price DL, Eberhart, CG, and Wong PC. Moderate reduction of γ-secretase attenuates amyloid burden and limits mechanism-based liabilities J. Neuroscience, 2007 27(40):10849-59

Li T, Wen H, Brayton C, Das P, Smithson LA, Fauq A, Fan X, Crain BJ, Price DL, Golde TE, Eberhart CG, Wong PC. EGFR and notch pathways participate in the tumor suppressor function of gamma -secretase. J Biol Chem. 2007, 282(44):32264–32273.

Chow VW, Savonenko, AV, Melnikova T, Kim H Price DL, Li T, and Wong PC. Modeling an anti-amyloid combination therapy for Alzheimer’s disease. Sci. Transl. Med. 2010. 2, 13ra1 PMCID:PMC2852193

Li T, Li Y, Ahn K, Price DL, Sisodia SS, Wong PC. Increased expression of PS1 is sufficient to elevate the level and activity of &gamma-secretase in vivo. Plos ONE. 2011, 6(11):e28179.




Email martinl@jhmi.edu
Phone (410) 502-5170
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Lee J. Martin, Ph.D.

Primary Appointment in Pathology; Secondary Appointment in Neuroscience
Member, Graduate Program in Neuroscience; Member, Graduate Program in Pathobiology


Mechanisms of Neuronal Death in Adult and Developing Central Nervous System. In the human central nervous system (CNS), neurons degenerate after acute neurological insults resulting from stroke and cardiac arrest and during the progression of adult-onset neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. Only certain groups of neurons degenerate in each of these neurological disorders, and this phenomenon is called selective vulnerability. In order to therapeutically manage and prevent this neurodegeneration, it is important to identify the cellular and molecular mechanisms of selective neuronal vulnerability and death. In my laboratory, we are testing the hypothesis that selective vulnerability is dictated by brain regional connectivity, mitochondrial function, and oxidative stress and is mediated by excitotoxic cell death resulting from abnormalities in excitatory, glutamatergic signal transduction pathways, including glutamate transporters and glutamate receptors as well as their downstream intracellular signaling molecules. We are also investigating the contribution of neuronal/glial apoptosis and necrosis as cell death pathways in animal (including transgenic mice) models of acute and progressive neurodegeneration. We use a variety of anatomical and molecular neurobiological approaches, including neuronal tract-tracing techniques, immunocytochemistry, immunoblotting, antipeptide antibody production, transmission electron microscopy, and DNA analysis to determine the precise regional and cellular vulnerabilities and the synaptic and molecular mechanisms that result in selective neuronal degeneration.

Publications
Martin LJ: Neuronal cell death in nervous system development, disease, and injury. Int. J. Mol. Med. 7: 455-478, 2001.

Martin LJ and Liu Z: Injury-induced spinal motor neuron apoptosis is preceded by DNA single-strand breaks and is p53- and bax-dependent. J. Neurobiol. 50: 181-197, 2002 (Journal Cover Illustration).

Lesuisse C and Martin LJ: Immature and mature cortical neurons engage different apoptotic mechanisms involving caspase-3 and the mitogen-activated Protein kinase pathway. J Cereb. Blood Flow Metab. 22: 935-950, 2002.

Martin LJ, Price AC, McClendon KB, Al-Abdulla NA, Subramaniam JR, Wong PC and Liu Z: Early events of target deprivation/axotomy-induced neuronal apoptosis in vivo: oxidative stress, DNA damage, p53 phosphorylation and subcellular redistribution of death proteins. J. Neurochem. 85: 234-247, 2003.




Email tmelnik1@jhmi.edu
Phone (410) 502-2819
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Tatiana Melnikova, Ph.D.

Primary Appointment in Pathology


The main focus of our laboratory is the investigation of different animal models of Alzheimer's disease and the contribution of different Aß species to the development of behavioral and cognitive deficits during disease progression. By using different experimental treatments or genetic manipulations to alter Aß production, we analyze the reversibility of the cognitive deficits at different stages of disease. Animal models of familiar form of Alzheimer’s disease include conventional transgenic mouse models (APPswe,PS1dE9; APPswe/PS1dE9/Cox2, etc) and conditional mouse models ( APPsi:tTA). In the latter APP production is driven by a tetracycline transactivator expressed in the brain areas involved in learning and memory. The overexpression of APP transgene is modulated by tetracycline analog, doxycycline (DOX). In our recent study we demonstrated that acute suppression of new APPsi/Aß production in the APPsi:tTa mice with high levels of plagues accumulation significantly improved performance in short-term spatial memory tasks. These changes upon continued suppression were transformed in further improvement in more demanding tasks that assess long-term spatial and working memories. However, deficits in episodic –like memory and cognitive flexibility were more persistent and were still present after three weeks of DOX treatment as well as high plaques burden. Cognitive improvements coincided with dramatic reduction of different APP metabolites (full-length APP, soluble APP ectodomains, and APP C-terminal fragments) at the end of experiment. Despite the fact that animal models couldn’t recapitulate all aspects of the human disease they allow us to dissect different stages of disease progression and define the sensitive periods when it is still possible to delay or reverse cognitive deficits.

In other projects we are looking at the pathogenic mechanisms involved in autism spectrum disorder and investigating the pathways implicated in schizophrenia-like endopenotypes. In particularly, we are studying BACE1- dependent NRG1-ErbB4 signaling interactions with glutamatergic receptors pathways. We found that the mice with deletion of BACE1 (?-site APP cleavage enzyme1) exhibited multiple behavioral endophenotypes related to schizophrenia such as deficits in prepulse inhibition, novelty-induced hyperactivity, sensitivity to a psychostimulant, disturbances in social interactions, and cognitive deficits. We continue this work by testing the hypothesis that changes in BACE1/NRG1 signaling could be primary or secondary to the alterations in glutamatergic mechanisms implicated in schizophrenia. To this end, we compare two different models of schizophrenia. As a first model, we are using BACE1 knockout mice, in which changes in BACE1/NRG1 signaling are primary. In the second model we are using PCP treatment during early development that results in primary alterations in glutamatergic pathway.

Publications

Jankowsky JL, Melnikova T, Fadale DJ, Xu GM, Slunt HH, Gonzales V, Younkin LH, Younkin SG, Borchelt DR, Savonenko AV. Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer's disease. The Journal of Neuroscience. 2005; 25: 5217-5224.

Savonenko AV, Xu GM, Melnikova T, Morton JL, Gonzales V, Wong M, Price D L, Tang F, Markowska AL, Borchelt DR. Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer's disease: relationship to ß-amyloid deposition and neurotransmitter abnormalities. Neurobiology of Disease. 2005; 18: 602-617.




Email frodrig4@jhmi.edu
Phone (443) 287-6646
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Fausto J. Rodriguez, M.D.

Primary Appointment in Pathology; Secondary Appointment in Oncology


My clinical and research interests focus on the identification of diagnostic, prognostic, and therapeutic biomarkers in primary brain tumors. My current research activities aim to characterize molecular changes and signaling pathway alterations associated with the development of pediatric gliomas, as well as phenotypic characterization of murine models of CNS neoplasia. As part of a multidisciplinary effort, one of my main goals is to integrate classic histopathologic analyses with current ancillary and molecular data obtained through immunohistochemistry, microarray profiling, molecular cytogenetics, and genomic sequencing.

Publications

Rodriguez FJ, Gamez JD, Vrana JA, Theis JD, Giannini C, Scheithauer BW, Parisi J, Lucchinetti CF, Pendlebury WW, Dogan A. Immunoglobulin Derived Depositions in the Nervous System: Novel Mass Spectrometry Application for Protein characterization in Formalin-Fixed tissues. Lab Investig 2008;88:1024-37.

Rodriguez FJ, Giannini C, Asmann YW, Sharma MK, Perry A, Tibbetts KM, Jenkins RB, Scheithauer BW, Anant S, Jenkins S, Eberhart CG, Sarkaria JN, Gutmann DH. Gene Expression Profiling of NF1-associated and Sporadic Pilocytic Astrocytoma Identifies ALDH1L1 as an Underexpressed Candidate Biomarker in Aggressive Astrocytoma Subtypes. J Neuropathol Exp Neurol 2008;12:1194-1204

Bender AM, Collier LS, Rodriguez FJ, Tieu C, Larson JD, Halder C, Mahlum E,. Kollmeyer TM, Akagi K, Sarkar G, Largaespada DL, Jenkins RB. Sleeping Beauty-mediated somatic mutagenesis implicates Csf1 in the formation of high grade astrocytomas. Cancer Res 2010; 70:3557-65.

Rodriguez EF, Scheithauer BW, Giannini C, Rynearson A, Cen L, Hoesley B, Gilmer-Flynn H, Sarkaria JN, Jenkins S, Long J, Rodriguez FJ. PI3K/AKT Pathway Alterations are Associated With Clinically Aggressive and Histologically Anaplastic Subsets of Pilocytic Astrocytoma. Acta Neuropathol 2011;121:407-20.

Rodriguez FJ, Orr B, Ligon K, Eberhart CG. Neoplastic cells are a rare component in human glioblastoma microvasculature. Oncotarget 2012;3:98-106.




Email troncoso@jhmi.edu
Phone (410) 502-5165
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Juan C. Troncoso, M.D.

Primary Appointment in Pathology; Secondary Appointment in Neurology
Member, Graduate Program in Pathobiology


My research activities focus on the neuropathology, pathogenesis and therapy of neurodegenerative disorders, i.e. Alzheimer's, Parkinson's, and Huntington's disease, and the neuropathology of aging. These activities encompass morphological studies of human brains and clinical-pathological correlations, along with investigations of the pathogenesis of neurodegenerative disorders in relevant genetically engineered mouse models and in vitro systems. These research activities are funded by the JHU Alzheimer's Disease Research Center (NIA), Morris K. Udall Parkinson's Disease Center of Excellence (NINCDS), the Huntington's Disease Center (NINCDS).

Studies of human brain include detailed clinical-pathological correlations on diseased and control subjects who have had thorough neurological and cognitive assessments. In recent years, my collaborators and I have begun to define the early stages of Alzheimer's Disease (AD), including preclinical and mild cognitive impairment (MCI) stages. Using unbiased stereology approaches, a particular strength of my laboratory, we have shown that the number of neurons of the hippocampus remains stable in preclinical AD.

Investigations of AD immunotherapy, funded by a grant of the Alzheimer's Association, represent a new and very exciting field of research in my laboratory. In collaboration with my colleague David Borchelt, Ph.D., we are studying the effects of immunization with A-beta or the passive transfer of A-beta antibodies in transgenic mouse models of AD. This investigation has several facets that include the development of new vaccine formulations to reduce the risk of encephalomyelitis, neuropathological and behavioral assessments, and investigations of the mechanisms underlying the beneficial effects of A-beta immunization on A-beta deposition and cognitive/behavioral performance of affected animals.

Publications

West MJ, Coleman PD, Flood DG, Troncoso JC. Differences in the pattern of hippocampal neuronal loss in normal aging and Alzheimer's disease. Lancet 344:769-772, 1994.

Troncoso JC, Martin LJ, Dal Forno G, Kawas CH. Neuropathology in controls and demented subjects from the Baltimore Longitudinal Study of Aging. Neurobiol. Aging 17:365-371, 1996.

Vehmas AK, Borchelt DR, Price DL, McCarthy D, Wills-Karp M, Peper M, Rudow G, Luyinbazi J, Siew L, Troncoso J. Beta-amyloid peptide vaccination results in marked changes in serum and brain A-beta levels in APPswe/PS1E9 mice, as detected by SELDI-TOF-based ProteinChip® technology. DNA and Cell Biology 20:713-721, 2001.

West MJ, Kawas CH, Stewart WF, Rudow GL, Troncoso JC. Hippocampal neurons in pre-clinical Alzheimer’s disease. Neurobiology of Aging 25(9):1205-12, 2004.

Pletnikova O, West N, Lee MK, Rudow G, Skolasky RL, Dawson TM, Marsh L, Troncoso JC. Aβ deposition enhances cortical α-synuclein lesions in Parkinson’s disease. Accepted for publication in Neurobiology of Aging.




Email WONG@jhmi.edu
Phone (410) 502-5168
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Philip C. Wong, Ph.D.

Primary Appointment in Pathology; Joint Appointment in Neuroscience
Member, Graduate Program in Cellular and Molecular Medicine; Member, Graduate Program in Neuroscience; Member, Graduate Program in Pathobiology


My research program is designed to understand the molecular mechanisms of neurodegenerative diseases, particularly Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS).

A major pathological hallmark of AD is the deposition of a toxic peptide, termed beta-amyloid (Ab) that is liberated from a parental beta-amyloid precursor protein (APP) by two enzymatic cleavages, termed beta- and gamma-secretase. We have previously hypothesized that beta-secretase (also called BACE1), enriched in neurons of the central nervous system (CNS), is a major determinant that predisposes the brain to Abeta amyloidogenesis and demonstrated that the physiologically high levels of BACE1 activity coupled with low levels of BACE2 and beta-secretase activities in neurons are major contributors to the accumulation of Abeta in the CNS while other tissues and organs are spared. Significantly, deletion of BACE1 in APPswe; PS1dE9 mice prevents Ab deposition. Moreover, deletion of BACE1 restored age-associated cognitive abnormalities that occur in this model of Ab amyloidosis. Recently, we have begun efforts to develop inducible mouse models of BACE1 or RNAi approaches to suppress expression of BACE1 in models of amyloidosis in order to examine issues regarding the reversibility of Ab deposition on brain repair. It has been shown that the presenilins (PS1 and PS2), which when mutated cause familial AD, participate in the intramembraneous proteolysis of several type I transmembrane proteins, including APP and Notch1. The current view is that the gamma-secretase complex is comprised of at least PS, Nicastrin, APH-1 and PEN-2. Our deletion analyses of PS1, Nicastrin and Aph-1 established that each of these membrane proteins is an essential component of the gamma-secretase complex. Current studies are aimed towards defining the exact role for each of these components in complex assembly and activity of this interesting enzyme complex as well as testing their therapeutic potentials as drug targets for AD.

Recently, missense mutations have been linked to the p150 subunit of the dynactin complex in ALS. The dynactin complex is a high molecular weight multi-protein complex that was originally shown to differentially co-purify with dynein, the molecular motor responsible for retrograde transport along microtubules. Defects in axonal transport have been proposed as a possible pathogenic mechanism in ALS. Since mutant dynactin is inherited in an autosomal dominant fashion, we hypothesize that the disease mechanism is associated with an adverse gain of function. To test whether the G59S mutant p150 subunit of the dynactin complex is sufficient to confer motor neuron disease in mice, we generated mutant p150 transgenic mouse models. This mouse model should be invaluable to clarify whether defects in axonal transport can be an important pathogenic mechanism in ALS.

Publications

Ma G, Li T, Price DL and Wong PC: Aph-1a is the principal mammalian Aph-1 isoform present in gamma-secretase complexes during embryonic development. J. Neuroscience, in press.

Li T, Ma G, Cai H, Price DL, Wong PC: Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate Notch Signaling, and for processing and trafficking of beta-APP in mammals. J. Neuroscience 23: 3272-3277, 2003.

Subramaniam JR, Lyons WE, Liu J, Bartinakas TB, Rothstein J, Price DL,Cleveland DW, Gitlin JD and Wong PC: Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading. Nature Neuroscience 5: 301-307, 2002.

Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL and Wong PC: BACE1 is the major beta-secretase for generation of Ab peptides by neurons. Nature Neuroscience 4: 233-234, 2001.

Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJS, Trumbauer ME, Chen HY, Price DL, Van der Ploeg LHT and Sisodia SS: Presenilin 1 is required for Notch1 and Dll1 expression in the paraxial mesoderm. Nature 387: 288-292, 1997.



 


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