Neuroscience Discipline

Center for Neurodegenerative Diseases and Therapeutics

Dr. Marr received his undergraduate degree in applied biochemistry from the University of Guelph, Guelph, Ontario, Canada. Afterward, he did his graduate work in the laboratory of Dr. Frank Graham at McMaster University in Hamilton, Ontario, Canada where he worked on gene therapy for cancer. After receiving his PhD in Molecular Biology Genetics and Cancer from McMaster he moved to the Salk Institute for Biological Studies in La Jolla California. There his work in the laboratory of Dr. Inder Verma was primarily on the application of gene transfer technology to the study and treatment of Alzheimer’s disease.

Research Interests

The overlying area of Dr. Marr’s interests lay in the study of neurodegenerative diseases. More specifically his focus is on Alzheimer’s disease and the use of gene transfer vectors as a tool to investigate specific gene function(s) in the brain as it relates to Alzheimer’s. The derivation of potentially new therapeutic approaches to Alzheimer’s disease is also an area of focus for Dr. Marr, as well as the role of Alzheimer’s related genes in the process of traumatic brain injury. Finally, his laboratory has been working on the use in induced human neurons to model aspects of dementia and for their application to regenerative medicine.

He has been awarded the Lee Nielson Roth Award for Cancer Research from McMaster University (1997), and received awards from the Medical Research Council of Canada (1998), and the Canadian Institutes of Health Research (2000). He also received an Excellence in Research Award from the American Society for Gene Therapy (2003).

Current Research Support

NIH/NIA (RF1 AG065628), Co-I: R.A. Marr (PI: GE Stutzmann). “Intracellular organelle deficits driving Alzheimer’s disease.” The major goal of this study is to determine the role of calcium dysregulation in conjunction with lysosomal and mitochondrial dysfunction in human induced neurons as it related to dementia. Period of support: 09/01/2020 - 08/31/2024.

NIH/NINDS (RO1 NS100514), Co-I: R.A. Marr (MPI: D.A. Peterson). “Reprogramming Cell Fate for Repair.” The major goal of this study is to develop procedures for producing induced neurons from tissue resident glia and determine their characteristics and function as well as potential for neural tissue regeneration. Period of support: 6/15/17 - 5/31/22

Past Research Support

Schweppe Foundation Career Development Award (4/01/07-3/31/09). Role: PI
“SEP (NEP2) and Aβ Degradation: Assessment of in vivo role in protecting against Alzheimer disease.”
The goal of this project was to determine if endogenous mouse SEP expression is involved in A degradation.

Alzheimer’s Association New Investigator Research Grant [NIRG-08-89784] (11/1/08-10/31/10). Role: PI
“Investigation of the role of MMEL (NEP2) in protection from Alzheimer's disease.”
The goal of this project was to examine to role of MMEL expression in AD and its therapeutic potential.

Alzheimer’s Disease Drug Discovery Foundation Grant [#290201] (3/01/09-2/28/10) Role: PI
“Investigation of the role of SEP (NEP2) in controlling cerebral beta-amyloid pathology.”
The goal of this project was to identify agents that can induce A degradation and to target A degrading activity across the blood-brain-barrier into the CNS.

NIH-NIA R01AG033570 (2009-2013) PI: Orly Lazarov. Role: Co-I
“The role of PS1 in regulation of adult neurogenesis in the intact and Alzheimer’s brain”
The goal of this project is to examine the role of presenilin-1 in adult neurogenesis.

NIH-NIA 2R01AG020047-06A2 (2010-2014) PI: Daniel Peterson. Role: Co-I
“Stem cells for brain repair.”
The goal of this project is to modify, promote, and manipulate endogenous neural stem cells.

DePaul/RFUMS Alliance. MPI: R.A. Marr, M. Glucksman & E. Norstrom.
“The APP interactome: Translating New Targets in Alzheimer’s Disease.”
APP interacting targets will be identified and expressed/repressed in vivo using viral vectors.
Period of support: 09/01/13-06/30/16.

DePaul/RFUMS Alliance. MPI: R.A. Marr, D. Kozlowski, D. Peterson, G.E. Stutzmann, J. Urban.
“Chronic effects of repeat concussive impacts on brain injury and recovery.”
The effects of multiple mild closed-head TBI on behavior, pathology, neurogenesis, and anxiety will be determined.
Period of support: 12/01/15-03/31/17.

NIH/NIA (R21 AG048615), MPI: G. E. Stutzmann & R.A. Marr.
“Validating novel ryanodine receptor-targeted compounds for AD therapeutics.”
Drugs which alter ryanodine receptor targets with be screened on viral vector induced neurons from AD patients and then used for in vivo therapy in mice.
Period of support: 04/15/15-03/31/17.

NIH/NINDS (R21 NS093570), PI: R.A. Marr. Nep-like endopeptidases in traumatic brain injury and the associated dementias.” Nep-like knockout and transgenic mice will be used to examine the role of these genes in the process of traumatic brain injury and chronic traumatic encephalopathy. Period of support: 08/01/16 - 05/31/18.

DePaul/RFUMS Alliance. MPI: R.A. Marr, D. Kozlowski, D. Peterson, G.E. Stutzmann, J. Urban. “Chronic effects of repeat concussive impacts on brain injury and recovery.” The effects of multiple mild closed-head TBI on behavior, pathology, neurogenesis, and anxiety will be determined. Period of support: 4/1/2017 - 6/30/2018.

Research Projects | Publications | Service

Research Projects

My work has primarily dealt with molecular mechanisms of neurodegeneration (mainly Alzheimer’s disease) with an emphasis on identifying molecular markers and therapies. Deficiencies in clearance of the amyloid-beta (Ab) peptide are thought to contribute to the development of Alzheimer’s disease (Marr et al. 2014. PMID: 25165447)(Marr RA (2014) Editorial on, “Amyloid-beta clearance in Alzheimer's disease”. Front. Aging Neurosci. 6:310.). The endopeptidase neprilysin (Nep) has been shown to be a key enzyme regulating Aß (Marr et al. 2003. PMID: 12657655). However, evidence suggests the existence of other proteases that contribute to the clearing of Aß (Marr et al. 2010. PMID: 20088804).Neprilysin-2 (Nep2) is the closest known homolog to Nep and is expressed in the brain; therefore, Nep2 is a good candidate for an enzyme that cooperates with Nep to control cerebral Aß levels. Our group has identified a new property for the Nep2 enzyme, in that it can degrade the Ab peptide in humans (Huang et al. 2008. PMID: 18571334). We also found that Nep2 functions in vivo to significantly reduce Ab peptide levels in the rodent brain (Hanson et al. 2010. PMID: 20941644; Hafez et al. 2011. PMID: 21224067). Finally, we showed that the expression and activity of Nep2 is altered in association with preclinical Alzheimer’s disease (Huang et al. 2012. PMID: 22008264). This finding suggests that Nep2 quantitation might serve as an early predictor of risk for developing the disease. My work on therapeutic applications to Alzheimer’s disease also extends to the use of antisense technology to specifically target genes linked to disease pathogenesis. Finally, in collaboration with DePaul University, I am also working on the therapeutic application of gene-manipulation of novel amyloid precursor protein (APP) interacting proteins (Philibert et al. 2014. PMID: 25346686) for Alzheimer’s disease.

In addition to my work as part of the neuroscience discipline, I am also a center investigator at the Center for Stem Cell and Regenerative Medicine here at RFUMS. My work with the center includes the investigation of the cross-talk between neurogenic pathways and neurodegeneration. Related to this, we have reported that gene transfer of the pro-neurogenic F-spondin gene reduced Alzheimer’s-like pathology in mice (Hafez et al. 2012. PMID: 22863679). Our interests also extend to the use of gene transfer vectors to “reprogram” cells in vitro and in vivo to produce induced neurons for disease modeling and therapeutic applications. Related to this we have used retroviral vectors for the manipulation of endogenous progenitor cell fate in the brain (Klempin et al. 2012. PMID: 22162276). Lastly, this work has implications for the study and treatment of traumatic brain injury which we are pursuing in collaboration with investigators at DePaul University.

PUBLICATIONS

Peer Reviewed Publications

KC Maigler, TJ Buhr, CS Park, SA Miller, DA Kozlowski, RA Marr (2020). Assessment of the effects of altered amyloid-beta clearance on behavior following repeat closed-head brain injury in APP humanized mice. J Neurotrauma. doi: 10.1089/neu.2020.6989. PMID: 33176547

S Schrank, J McDaid, CA Briggs, S Mustaly-Kalimi, D Brinks, A Houcek, O Singer, V Bottero, RA Marr*, GE Stutzmann* (2020). Human-Induced Neurons from Presenilin 1 Mutant Patients Model Aspects of Alzheimer's Disease Pathology. Int J Mol Sci. 21(3):  21(3):1030. PMC7037274 *co-senior and co-corresponding authors     

Silveira Villarroel H, Bompolaki M, Mackay JP, Miranda Tapia AP, Michaelson SD, Leitermann RJ, Marr RA, Urban JH, Colmers WF. (2018) NPY Induces Stress Resilience via Downregulation of Ih in Principal Neurons of Rat Basolateral Amygdala. J Neurosci. 38(19):4505-4520. PMID: 29650696

Chang JL, Hinrich AJ, Roman B, Norrbom M, Rigo F, Marr RA, Norstrom EM, Hastings ML. (2018) Targeting Amyloid-β Precursor Protein, APP, Splicing with Antisense Oligonucleotides Reduces Toxic Amyloid-β Production. Mol Ther. 26(6):1539-1551. PMID: 29628304

Lim PH, Wert SL, Tunc-Ozcan E, Marr R, Ferreira A, Redei EE. (2018) Premature hippocampus-dependent memory decline in middle-aged females of a genetic rat model of depression. Behav Brain Res. pii: S0166-4328(17)31740-0.  PMID: 29490235

Jamnia N, Urban JH, Stutzmann GE, Chiren SG, Reisenbigler E, Marr R, Peterson DA, Kozlowski DA. (2017) A Clinically Relevant Closed-Head Model of Single and Repeat Concussive Injury in the Adult Rat Using a Controlled Cortical Impact Device. J Neurotrauma. 34(7):1351-1363. PMID: 27762651

AJ Hinrich, FM Jodelka, JL Chang, D Brutman, A Bruno, CA Briggs, BD. James, GE Stutzmann, DA Bennett, SA Miller, F Rigo, RA Marr, ML Hastings (2015). Therapeutic correction of apoER2 splicing in Alzheimer’s disease mice using antisense oligonucleotides. EMBO Molecular Medicine, 8(4):328-45. PMID: 26902204

JA Bonds, Y Kuttner-Hirshler, N Bartolotti, MK Tobin; M Pizzi, RA Marr, O Lazarov (2015). Presenilin-1 dependent neurogenesis regulates hippocampal learning and memory. PLoS One, 10(6):e0131266. PMID: 26098332

KD Philibert, RA Marr, EM Norstrom, MJ Glucksman (2014). Identification and characterization of Aβ peptide interactors in Alzheimer’s disease by structural approaches. Frontiers in Aging Neuroscience. 6(265): PMID: 25346686

DM Hafez, JY Huang, JC Richardson, E Masliah, DA. Peterson, RA. Marr^† (2012). F-spondin gene transfer improves memory performance and reduces amyloid-β levels in mice. Neuroscience, 223: 465–472. PMID: 22863679

F Klempin, RA Marr, DA Peterson (2012). Modification of Pax6 and Olig2 in adult hippocampal neurogenesis selectively induces stem cell fate and alters both neuronal and glial populations. Stem Cells, 30(3):500-9. PMID: 22162276

JY Huang, DM Hafez, BD James, DA Bennett, RA Marr^† (2012). Altered NEP2 expression and activity in mild-cognitive impairment and Alzheimer’s disease. Journal of Alzheimer’s Disease, 28(2):433-41. PMID: 22008264

A Bruno, J Huang, DA Bennett, RA Marr, GE Stutzmann, and M Hastings (2011). Altered ryanodine receptor expression in mild cognitive impairment and Alzheimer's disease. Neurobiology of Aging, 33(5):1001.e1–1001.e6. PMID: 21531043

BJ Spencer, RA Marr, R Gindi, R Potkar, S Michael, A Adame, E Rockenstein, IM Verma, E Masliah (2011). Peripheral delivery of a CNS targeted, metallo-protease reduces Aß toxicity in a mouse model of Alzheimer's disease. PLoS One, 6(1): 1-12 e16575. PMID: 21304989

A Gadadhar, RA Marr, O Lazarov (2011). Presenilin-1 regulates neural progenitor cell differentiation in the adult brain. Journal of Neuroscience, 31(7):2615-23. PMID: 21325529

D Hafez, JY Huang, AM Huynh, S Valtierra, E Rockenstein, AM Bruno, B Lu, L DesGroseillers, E Masliah, RA Marr^† (2011). Neprilysin-2 is an important beta-amyloid degrading enzyme. American Journal of Pathology, 178(1): 306-312. PMID: 21224067

LR Hanson, D Hafez, AL Svitak, RB Burns, X Li, WH Frey, and RA Marr^† (2010). Intranasal phosphoramidon increases beta-amyloid levels in wild-type and NEP/NEP2 deficient mice. Journal of Molecular Neuroscience, 178(1): 306-312. PMID: 20941644

O Lazarov, RA Marr (2009). Neurogenesis and Alzheimer's disease: At the crossroads. Experimental Neurology, 223:267-281. PMID: 19699201

J Rose, L Crews, E Rockenstein, A Adame, M Mante, L Hersh, FH Gage, B Spencer, R Potkar, R Marr, and E Masliah (2009). Neuropeptide Y fragments derived from neprilysin processing are neuroprotective in a transgenic model of Alzheimer's disease. Journal of Neuroscience, 29(4):1115–1125. PMID: 19176820

B Spencer , RA Marr , E Rockenstein , L Crews , A Adame , R Potkar , C Patrick , FH Gage , IM Verma and E Masliah (2008). Long-term neprilysin gene transfer is associated with reduced levels of intracellular Abeta and behavioral improvement in APP transgenic mice. BMC Neuroscience, 9:109. PMID: 19014502

JY Huang, AM Bruno, CA Patel, AM Huynh, KD Philibert, MJ Glucksman, RA Marr^† (2008). Human membrane metallo-endopeptidase-like protein (MMEL) degrades both Ab₄₂ and Ab₄₀. Neuroscience, 155(1):258-62. PMID: 18571334

SS El-Amouri, H Zhu, J Yu, R Marr, IM Verma, MS Kindy (2008). Neprilysin: An enzyme candidate to slow the progression of Alzheimer's disease. American Journal of Pathology, 172(5):1332-1344. PMID: 18403590

I Hovatta, RS Tennant, R Helton, RA Marr, O Singer, JM Redwine, EE Schadt, JA Ellison, IM Verma, DJ Lockhart and C Barlow (2005). Glyoxalase 1 and glutathione reductase regulate anxiety in inbred mouse strains. Nature, 438(7068):662-6. PMID: 16244648

RA Marr*, O Singer*, E Rockenstein, L Crews, NG Coufal, FH Gage, IM Verma, and E Masliah (2005). Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nature Neuroscience, 8(10):1343-9. PMID: 16136043 *both authors contributed equally

JC Dodart, RA Marr, M Koistinaho, BM Gregersen, S Malkani, IM Verma, SM Paul (2005). Gene delivery of human apolipoprotein E alters brain Ab burden in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. U S A., 104(4):1211-1216. PMID: 15657137

M Hashimoto, E Rockenstein, M Mante, L Crews, P Bar-On, FH Gage, R Marr, and E Masliah (2004). An antiaggregation gene therapy strategy for Lewy body disease utilizing b-synuclein lentivirus in a transgenic model. Gene Therapy, 11(23): 1713-1723. PMID: 15483670

HM Kankkonen, E Vähäkangas, RA Marr, T Pakkanen, A Laurema, P Leppänen, J Jalkanen, IM Verma, S Ylä-Herttuala (2004). Long-term lowering of serum cholesterol levels in LDL-receptor deficient WHHL rabbits by gene therapy. Molecular Therapy, 9(4):548-556. PMID: 15093185

RA Marr, H Guan, E Rockenstein, M Kindy, FH Gage, I Verma, E Masliah, LB Hersh (2004). Neprilysin regulates amyloid-b peptide levels. Journal of Molecular Neuroscience, 22(1-2):5-11. PMID: 14742905

RA Marr, E Rockenstein, A Mukherjee, MS Kindy, LB Hersh, FH Gage, IM Verma, and E Masliah (2003). Neprilysin gene transfer reduces human amyloid pathology in transgenic mice. Journal of Neuroscience, 23(6):1992-1996. PMID: 12657655 (Featured in The Lancet 361(9363):1107 and Drug Discovery Today 8(11): 474).

Z Chen, H Huang, T Chang, S Carlsen, A. Saxena, R Marr, Z Xing, J Xiang (2002). Enhanced HER-2/neu-specific antitumor immunity by cotransduction of mouse dendritic cells with two genes encoding HER-2/neu and alpha tumor necrosis factor. Cancer Gene Therapy, 9(9): 778-786. PMID: 12189528

RA Marr, M Hitt, J Gauldie, WJ Muller, and FL Graham (1999). A p75 TNF receptor specific mutant of murine TNFa expressed from an adenovirus vector induces an antitumour response with reduced toxicity. Cancer Gene Therapy, 6(5): 465-474. PMID: 10505857

PJ Sime, RA Marr, D Gauldie, Z Xing, BR Hewlett, FL Graham, and J Gauldie (1998). Transfer of tumour necrosis factor-alpha to rat lung induces severe pulmonary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor-beta1 and myofibroblasts. American Journal of Pathology, 153(3): 825-832. PMID: 9736031

RA Marr, M Hitt, WJ Muller, J Gauldie, and FL Graham (1998). Tumour therapy using adenovirus vectors expressing human TNFa. International Journal of Oncology, 12(3): 509-515. PMID: 9472086

XF Lei, Y Ohkawara, MR Stampfli, C Mastruzzo, RA Marr, D Snider, Z Xing, and M Jordana (1998). Disruption of antigen-induced inflammatory responses in CD40 ligand knock out mice. Journal of Clinical Investigations, 101(6): 1342-1353. PMID: 9502776

RA Marr, CL Addison, D Snider, WJ Muller, J Gauldie, and FL Graham (1997). Tumour immunotherapy using an adenoviral vector expressing a membrane-bound mutant of murine TNFa. Gene Therapy, 4(11): 1181-1188. PMID: 9425441

^† corresponding author

Reviews

RA Marr†, DM Hafez (2014). Amyloid-beta and Alzheimer’s disease: The role of neprilysin-2 in amyloid-beta clearance. Frontiers in Aging Neuroscience. 6(187):1-7. PMID: 25165447

O Lazarov† and RA Marr† (2013). Of mice and men: Neurogenesis, cognition and Alzheimer’s disease. Frontiers in Aging Neuroscience. 5:43 doi: 10.3389/fnagi.2013.00043. PMID: 23986699

RA Marr, RM Thomas, and DA Peterson (2010). Insights into neurogenesis and aging: Potential therapy for degenerative disease? Future Medicine, 5(4): 527-541. PMID: 20806052

Invited - RA Marr† and BJ Spencer (2010). NEP-like endopeptidases and Alzheimer’s disease. Current Alzheimer’s Research, 7:223-229. PMID: 20088804

O Lazarov, RA Marr (2009). Neurogenesis and Alzheimer's disease: At the crossroads. Experimental Neurology, 223:267-281. PMID: 19699201

B Spencer, E Rockenstein, L Crews, R Marr, E Masliah (2007). Novel strategies for Alzheimer's disease treatment. Expert Opin Biol Ther. 7(12):1853-67. PMID: 18034651

J Gauldie, PJ Sime, Z Xing, B Marr, and GM Tremblay (1999). TGFß gene transfer to the lung induces myofibroblast presence and pulmonary fibrosis. Current Topics in Pathology, 93: 35-45. PMID: 10339897

Editorials

Marr RA (2014). Editorial on, “Amyloid-beta clearance in Alzheimer’s disease.” Frontiers in Aging Neuroscience. doi: 10.3389/fnagi.2014.00310.

Manuscripts Submitted or in Preparation

S Bazarek, A Mehta, R Patel, CA Briggs, S Chakroborty, E Reisenbigler, GE Stutzmann, RA Marr, and DA Peterson (2015). In vivo conversion of resident adult cortical oligodendrocyte progenitor cells to cortical projection neurons. In preparation.

Invited Book Chapters

Marr, RA (2015). The Amyloid Beta Precursor Protein and Cognitive Function in Alzheimer’s Disease. In Genes, Environment and Alzheimer’s Disease, O. Lazarov and G Tesco, eds, Elsevier / Academic Press, Section I, Chapter 4, pp. 98-117.

Marr, RA (2011). MS: 133 | Neprilysin-2. In Handbook of Proteolytic Enzymes, 3^rd edition, ND Rawlings and G Salvesen, eds, Elsevier, Ch. 128, pp. 620-624.

Service

• Assistant Dean for Research
• Chair, Institutional Biosafety Committee
• Director, Molecular Quantification Laboratory