William C. Friday Distinguished Chair and Professor

Dr. Ben Bahr
Hippocampal slice

Repair Mechanisms in the Brain

The 100,000 Gbyte hard-drive we call our brain is a challenge to study, also making it a challenge to find therapeutic treatments against the numerous diseases that disrupt memory encoding and other brain functions. In my lab, slices of brain tissue are kept alive to examine neuronal connections responsible for memory processing as well as cellular maintenance pathways, and to study their vulnerability to pathogenesis. While the brain’s incredible density of synaptic connections allows for extraordinary memory capacity, the abundant synapses are also vulnerable to pathogenic over-activation. Such excitotoxic brain damage can occur in many disease states including stroke, traumatic injury, and seizure events. We are studying the pharmacological enhancement of endogenous compensatory pathways to offset the damage, and we found that positive modulation of internal repair mechanisms protects against the damaging effects of seizures and stroke-type excitotoxic insults.

Our other focus is to study age-related neurodegenerative disorders. Every 72 seconds someone in the U.S. develops Alzheimer’s disease (AD) due to suspected imbalances between protein production and protein clearance. Reducing Alzheimer-type protein accumulation is essential for slowing the progression of the disease. Lysosomes and their degradative enzymes (e.g. cathepsins) are known to respond to AD, likely in an attempt to offset the abnormal protein accumulations that cause a distinct cascade of synaptopathogenesis. To treat the impaired clearance of particular protein species, we discovered a new class of drugs that act as positive modulators of the lysosomal response, resulting in the up-regulation of cathepsins as well as neuroprotection in cultured brain slices and in mouse models of AD.

group

Members of the William C. Friday Laboratory

 

  • Ben A. Bahr, Ph.D. (PI; Depts. of Biology and Chemistry & Physics)
  • Heather Romine, M.B.A. (Lab Manager, Research Specialist)  
  • Karen Farizatto, Ph.D. (Postdoctoral Fellow)
  • Michael Almeida, M.S.  (Research Specialist)
  • Katherine Rentschler (Research Technician)
  • Ronald Long  (Research Technician)
  • Kaitlan Smith  (RISE Fellow; Glaxo Women in Science Scholar)
  • Ayanna Edwards  (RISE Fellow)
  • Jessica Rice  (Bio4990; summer RISE Researcher)
  • Christopher Norton  (Bio4990; summer RISE Researcher)
  • Yara Abumohsen  (Chemistry and Biology researcher)
  • Taylor Williams  (Bio4990 research)
  • Aseel Abumohsen  (Bio4990 research)
  • Britney Alcira  (Professor Sandefur collaboration)
Hippocampal Slice

Current Funding

W911NF-15-1-0432 Dept. of Defense Research & Education Program
Research Grant: The role of astrocyte activation in anticholinesterase-induced synaptic changes and behavioral deficits.

Bahr-USANA2016 USANA Health Sciences, Inc.
Contract: Expanding the search for protein clearance enhancers to promote healthy brain aging.

W911NF-14-2-0087 U.S. Army Research Office (HBCU/MI Program)
Research Grant: Sensitive Indicators and Risk Factors of Blast-Induced Neurodegeneration

W911NF-15-1-0053 U.S. Army Research Office (DOD Program)
Facility Grant: UNC Pembroke Laser Scanning Confocal Microscopy Facility

Bahr - Lys Mod Coins for Alzheimer’s Research Trust
Research Grant: Positive CatB modulation for an effective treatment to slow Alzheimer’s disease.

Northeastern University collaboration: Alzheimer’s Drug Discovery Foundation
subcontract: Fatty acid amide hydrolase inhibitors as Alzheimer’s disease medications

Recent Publications (from list of 150) 

(click here for publications available via NCBI)

Butler D, Hwang J, Estick C, Nishiyama A, Kumar SS, Baveghems C, Young-Oxendine HB, Wisniewski ML, Charalambides A, and Bahr BA (2011) Protective effects of positive lysosomal modulation in Alzheimer’s disease transgenic mouse models. PLoS One 6: e20501 LINK

Wisniewski ML, Hwang J, and Bahr BA (2011) Submicromolar Aβ42 reduces hippocampal glutamate receptors and presynaptic markers in an aggregation-dependent manner. Biochim Biophys Acta (Mol. Basis of Disease1812:1664-1674. LINK

Zheng X, Gessel MM, Wisniewski ML, Viswanathan K, Wright DL, Bahr BA, and Bowers MT (2012) Z-Phe-Ala-diazomethylketone (PADK) disrupts and remodels early oligomer states of the Alzheimer disease Aβ42 protein. J Biol Chem287:6084-6088. LINK

Naidoo V, Karanian DA, Vadivel SK, Locklear JR, Wood JT, Nasr M, Quizon PMP, Graves EE, Shukla V, Makriyannis A, and Bahr BA (2012) Equipotent inhibition of fatty acid amide hydrolase and monoacylglycerol lipase – dual targets of the endocannabinoid system to protect against seizure pathology. Neurotherapeutics 9:801-813. LINK

Bahr BA, Wisniewski ML, and Butler D (2012) Positive lysosomal modulation as a unique strategy to treat age-related protein accumulation diseases. Rejuvenation Res 15:189-197. LINK

Viswanathan K, Hoover DJ, Hwang J, Wisniewski ML, Ikonne US, Bahr BA, and Wright DL (2012) Nonpeptidic lysosomal modulators derived from Z-Phe-Ala-diazomethylketone for treating protein accumulation diseases. ACS Med Chem Lett 3:920-924.  LINK

Hoffmann DB, Williams SK, Bojcevski J, Müller A, Stadelmann C, Naidoo V, Bahr BA, Diem R, and Fairless R (2013) Calcium influx and calpain activation mediate preclinical retinal neurodegeneration in autoimmune optic neuritis. J Neuropathol Exp Neurol72:745-757. LINK

Filipovic R, Kumar SS, Bahr BA, and Loturco J (2014) Slice culture method for studying migration of neuronal progenitor cells derived from human embryonic stem cells (hESC). Curr Protoc Stem Cell Biol 29:1H.7.1-1H.7.14. LINK

Maltecca F, Baseggio E, Consolato F, Mazza D, Podini P, Young SM Jr, Drago I, Bahr BA, Puliti A,  Codazzi F, Quattrini A, and Casari G (2015) Purkinje neuron Ca2+ influx reduction rescues ataxia in the spinocerebellar ataxia type 28 (SCA28) model. J Clin Invest125:263-274. LINK

Carrasco DI, Bahr BA, Seburn KL, and Pinter MJ (2016) Abnormal response of distal Schwann cells to denervation in a mouse model of motor neuron disease. Exp Neurol 278:116-126. LINK

Smith M, Piehler T, Benjamin R, Farizatto KL, Pait MC, Almeida MF, Ghukasyan VV, and Bahr BA (2016) Blast waves from detonated RDX explosive reduce GluR1 and synaptophysin levels in hippocampal slice cultures. Exp Neurol 286:107-115. LINK

Farizatto KLG, Ikonne US, Almeida MF, Ferrari MFR, and Bahr BA (2017) Aβ42-mediated proteasome inhibition and associated tau pathology in hippocampus are governed by a lysosomal response involving cathepsin B: Evidence for protective crosstalk between protein clearance pathways. PLoS ONE 12:e0182895. LINK

Farizatto KLG, McEwan SA, Naidoo V, Nikas SP, Shukla VG, Almeida MF, Byrd A, Romine H, Karanian DA, Makriyannis A, and Bahr BA (2017) Inhibitor of endocannabinoid deactivation protects against in vitro and in vivo neurotoxic effects of paraoxon. J Mol Neuroscience 63:115-122. LINK

Piehler T, Zander N, Banton R, Benjamin R, Sparks R, Byrnes K, Duckworth J, and Bahr BA (2017) High speed imaging techniques to study effects of pressure waves from detonating explosive charges on biological materials. Dynamic Behavior of Materials 1:123-126.

Farizatto KLG and Bahr BA (2017) Paraoxon: An anticholinesterase that triggers an excitotoxic cascade of oxidative stress, adhesion responses, and synaptic compromise. Eur Sci J 13 (Oct. suppl.): 29-37. LINK

Romine H, Rentschler KM, Smith K, Edwards A, Colvin C, Farizatto KLG, Pait MC, Butler D, and Bahr BA (2017) Potential Alzheimer’s disease therapeutics among weak cysteine protease inhibitors exhibit mechanistic differences regarding extent of cathepsin B up-regulation and ability to block calpain. Eur Sci J 13 (Oct. suppl.): 38-59. LINK

Piehler T, Zander N, Banton R, Smith M, Romine H, Benjamin R, Byrnes K, Duckworth J, and Bahr BA (2018) Effects on neurons and hippocampal slices by single and multiple primary blast pressure waves from detonating spherical cyclotrimethylenetrinitramine (RDX) explosive charges. Military Med, in press.

Simões AP, Silva CG, Marques JM, Pochmann D, Porciúncula LO, Ferreira S, Oses JP, Beleza RO, Real JI, Köfalvi A, Bahr BA, Lerma J, Cunha RA, Rodrigues RJ (2018) Glutamate-induced and NMDA receptor-mediated neurodegeneration entails P2Y1 receptor activation. Cell Death Disease, in press.

Miquel S, Champ C, Day J, Aarts E, Bahr BA, Bakker M,  Bánáti D, Calabrese V, Cederholm T, Cryan J, Dye L, Farrimond JA, Korosi A, Layé S, Maudsley S, Milenkovic D, Mohajeri MH, Sijben J, Solomon A, Spencer JPE, Thuret S, Vanden Berghe W, Vauzour D, Vellas B, Wesnes K, Willatts P, Wittenberg R, and Geurts L (2018) Poor cognitive ageing: Vulnerabilities, mechanisms and the impact of nutritional interventions. Ageing Res Rev 42:40-55. LINK

Wang C, Telpoukhovskaia MA, Bahr BA, Chen X, and Gan L (2018) Endo-lysosomal dysfunction: a converging mechanism in neurodegenerative diseases. Current Opinion Neurobiol 48:52-58. LINK

Previous Undergraduate Researchers (RISE Fellows*; COMPASS Scholars#):

  • Joanna Cooper* (NCBC Fellow)
  • Hollie Young* (Gordon Conference Carl Storm Fellow)
  • David Blake
  • Emily Graves* 
  • Christopher Visser
  • Rebecca Howell* (NCBC Fellow)
  • Daisy Irra*
  • Jasmine Robinson*
  • Sarah Gambrel*
  • Josie Torrence*
  • Vivian Anunobi*
  • Arieana Van Allen 
  • Tyler Loehr*
  • Katharine Willoughby (Hawk Fellow)
  • Jody Long
  • Jasmine Rowlett*
  • Ginny Holland
  • Thomas Romine (Research & Engineering Apprenticeship)
  • John Locklear*
  • Pamela Marie Quizon (Research Assistant)   
  • Davita Brockington   
  • Ye Lin (undergrad research assistant)
  • Elizabeth Metzger (NC Space Grant/NASA Scholar)           
  • Robert Baldi
  • Kassie Conway*
  • Jordon Smink*
  • Louis Leonard
  • Paul Freeman*
  • M. Tyler Bullock (Research Engineering Apprenticeship) Robeson Early College Student
  • Sarah Ruiz* (NC Space Grant/NASA Scholar) 
  • Olivia Bullard* (Glaxo Scholar Women in Science) 
  • Marsalis Smith*
  • Armando Corona*
  • Julia McGee*
  • Samantha Suggs 
  • Rebecca Jackson
  • Veronica Robles
  • Kassie Conway*
  • Emily Suzanne Pope
  • Kayla J. Oxendine
  • Sonny Ruiz
  • Chaterria Perry*
  • Darian Duval
  • Joshua Ellerbe
  • Benson Mbugua
  • Kathlyn Stephens (PURC Research Fellow)    
  • Morgan C. Pait*
  • Lyndsie Elliott
  • Justin Showers
  • Matt MacDougall
  • Dalton Brooks
  • Christopher Long*
  • Justin Floyd
  • Marcus Sherman*
  • Ziporia Swift*
  • Aaron Byrd*
  • Sara A. McEwan*
  • Marilyn Louise Knotts
  • Paul J. Lascuna*#
  • Melissa Teel
  • Hailey Kelbaugh* (PURC Research Fellow)
  • Amanda Taylor
  • Amanda Bowman
  • Jasmine Sanderson
  • Kaitlan Smith; COMPASS Scholar and Summer Rise Scholar
  • Ronald Long; Summer Rise Scholar
  • Michael Joe Blair
  • Victor Cole
  • Sports Tweede
  • Katelynn Jacobs
  • Iliana Claudio; Robeson Early College (Senior Internship)
  • Ayanna Edwards*
  • Alyssa Norton
  • Camille Colvin
  • Ross Masters
  • Yara Abumohsen
  • Swathi Gadi
  • Nathan Jennings
  • Brenna Sifford
  • Frederick Feely II
  • Jullienne Lim;  (Honors College)
  • Jessica Rice
  • Christopher Norton; Summer Rise Scholar
  • Marica Thomas*
  • Britney Alcira
  • Georgian B Kailondo
  • Valerie A Odugba
  • Marianna Coppola
  • Aseel Abumohsen
  • Rawon Abumohsen
  • Asil Abudayeh
  • Sean Griffith
  • Taylor Williams