Pathology

Kenneth Hensley, Ph.D.


Kenneth Hensley, PhD

Associate Professor
University of Toledo Health Sciences Campus
Department of Pathology, MS #1090
3000 Arlington Avenue
Toledo, Ohio 43614-2598
Phone:  419-383-3442
Fax: 419-383-3066
Email:  Kenneth.Hensley@utoledo.edu

Education:

Ph.D. University of Kentucky

Research Interests:

The Hensley laboratory for neuropathology research studies the process of neuroinflammation with the goal of identifying conceptually novel protein or pathway targets that might be rationally exploited for neurodisease therapy development.

Neuroinflammation is a specific type of innate immune response that occurs in the brain during many, perhaps all, neurodegenerative diseases (including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and various motor neuron diseases). Neuroinflammation is manifest by activation of microglial cells in response to dysregulated cytokine networks and may be triggered by deposits of toxic protein or dead cell debris. For instance, amyloid peptides trigger a neuroinflammatory reaction in the Alzheimer’s disease-afflicted brain. Other proteins are implicated in other diseases, and different brain regions are affected, but the biochemical principles are very similar. Normally, microglia remove dead cells and pre-cancerous cells, but when triggered into a neuroinflammatory state the microglia attack neurons either directly or through “collateral damage”. The activated microglia release a host of toxic agents, especially free radicals (such as nitric oxide) that interfere with healthy neuron function.

Our main tool for studying neuroinflammation is the SOD1G93A transgenic mouse, which carries the human gene mutation responsible for hereditary amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). In this animal, the motor neurons of the brain and spinal cord deteriorate at 3-4 months of age and the mouse becomes paralyzed. We have developed a model for ALS pathogenesis in which a cytokine called TNFa drives the neuroinflammatory reaction. In addition to SOD1G93A mouse, we also use mammalian cell culture extensively in our research. Our cell culture tools include chick primary dorsal root ganglia (sensory) neurons; primary astrocytes; and EOC-20 murine microglia.

The most exciting recent outcome of our work was the discovery that an unusual central nervous system (CNS) metabolite called lanthionine ketimine (LK) possesses potent neuroprotective and neurotrophic effects mediated, in part, through a novel binding interaction with the brain protein CRMP2 (collapsing response mediator protein-2) (J. Neuroscience 2010). A cell-permeable LK-ethyl ester (LKE, invented in our lab and granted U.S. patent 7,683,055 in 2010) promotes neurite elongation in primary cell culture at low nanomolar concentrations. Furthermore, LKE protects neurons against glutamate or H2O2; suppresses microglial activation by TNFa; and protects motor neurons from microglial toxicity, all of which activities would benefit CNS tissue afflicted by ALS. We recently published that LKE slows disease progression in the SOD1G93A mouse model of ALS when administered late in the disease (Molecules 2010).

Due to its novel apparent mechanism of CRMP2 action, LKE potentially could become a “first-in-class” drug for treating neurodegeneration in ALS and other conditions. We are aggressively studying LKE and CRMP2 in order to address key questions: What is the metabolic origin of LK? How does LK affect CRMP2 to promote healthy neuron structure and function? What other molecules might bind CRMP2? What other pharmacological tactics might be employed to modulate CRMP2 pathways for therapeutic benefit? We are also collaborating with a number of groups in order to ascertain the full range of neurodegenerative conditions that might be amenable to treatment with LKE and similar CRMP2-binding agents, and to conduct crucial proof-of-concept studies that we hope will lead eventually to clinical development of these novel small molecule therapeutic candidates.  Dr. Hensley's work on ALS has been highlighted by the Muscular Dystrophy Association.

Representative recent publications (for a complete list, click here):
   Hensley K, Kursula P.  Collapsin Response Mediator Protein-2 (CRMP2) is a Plausible Etiological Factor and Potential Therapeutic Target in Alzheimer's Disease: Comparison and Contrast with Microtubule-Associated Protein Tau.  J Alzheimers Dis. 2016 Apr 15;53(1):1-14. PMID:    27079722
   Makani V, Jang YG, Christopher K, Judy W, Eckstein J, Hensley K, Chiaia N, Kim DS, Park J.BBB-Permeable, Neuroprotective, and Neurotrophic Polysaccharide, Midi-GAGR.  PLoS One. 2016 Mar 3;11(3):e0149715. doi: 10.1371/journal.pone.0149715. eCollection 2016.  PMID:   26939023
   Hensley K, Poteshkina A, Johnson MF, Eslami P, Gabbita SP, Hristov A, Venkova-Hristova K, Harris-White ME.  Autophagy modulation by lanthionine ketimine ethyl ester improves long-term outcome following central fluid percussion injury in the mouse.  J Neurotrauma. 2015 Nov 4. [Epub ahead of print].  PMID:     26530250
   Martins-de-Souza D; Cassoli JS; Nascimento JM; Hensley K; Guest PC; Pinzon-Velasco AM; Turck CW.  The protein interactome of collapsin response mediator protein-2 (CRMP2/DPYSL2) reveals novel partner proteins in brain tissue. [Review]  Proteomics Clinical Applications. 9(9-10):817-31, 2015
    Hensley K.  Detection of Protein Carbonyls by Means of Biotin Hydrazide-Streptavidin Affinity Methods.  Methods in Molecular Biology. 1314:95-100, 2015.
    Kadiiska MB; Peddada S; Herbert RA; Basu S; Hensley K; Jones DP; Hatch GE; Mason RP.  Biomarkers of oxidative stress study VI. Endogenous plasma antioxidants fail as useful biomarkers of endotoxin-induced oxidative stress.  Free Radical Biology & Medicine. 81:100-6, 2015
    Dupree JL; Polak PE; Hensley K; Pelligrino D; Feinstein DL.  Lanthionine ketimine ester provides benefit in a mouse model of multiple sclerosis.  Journal of Neurochemistry. 134(2):302-14, 2015
   Hensley K; Denton TT.  Alternative functions of the brain transsulfuration pathway represent an underappreciated aspect of brain redox biochemistry with significant potential for therapeutic engagement. [Review].  Free Radical Biology & Medicine. 78:123-34, 2015
    Venkova K; Christov A; Kamaluddin Z; Kobalka P; Siddiqui S; Hensley K.  Semaphorin 3A signaling through neuropilin-1 is an early trigger for distal axonopathy in the SOD1G93A mouse model of amyotrophic lateral sclerosis.  Journal of Neuropathology & Experimental Neurology. 73(7):702-13, 2014
    Gomez-Mejiba SE; Zhai Z; Della-Vedova MC; Munoz MD; Chatterjee S; Towner RA; Hensley K; Floyd RA; Mason RP; Ramirez DC.  Immuno-spin trapping from biochemistry to medicine: advances, challenges, and pitfalls. Focus on protein-centered radicals. [Review].  Biochimica et Biophysica Acta. 1840(2):722-9, 2014
    Makani V; Hall J; Qamar K; Jain P; Jang Y; Hensley K; Park JJ.  Tianeptine interferes with microtubule organization and hormone secretion of pheochromocytoma cells.  Molecular & Cellular Endocrinology. 381(1-2):175-87, 2013
    Hensley K; Gabbita SP; Venkova K; Hristov A; Johnson MF; Eslami P; Harris-White ME.  A derivative of the brain metabolite lanthionine ketimine improves cognition and diminishes pathology in the 3 x Tg-AD mouse model of Alzheimer disease.  Journal of Neuropathology & Experimental Neurology. 72(10):955-69, 2013
    Towner RA; Smith N; Saunders D; Lupu F; Silasi-Mansat R; West M; Ramirez DC; Gomez-Mejiba SE; Bonini MG; Mason RP; Ehrenshaft M; Hensley K.  In vivo detection of free radicals using molecular MRI and immuno-spin trapping in a mouse model for amyotrophic lateral sclerosis.  Free Radical Biology & Medicine. 63:351-60, 2013
    Floyd RA; Castro Faria Neto HC; Zimmerman GA; Hensley K; Towner RA.  Nitrone-based therapeutics for neurodegenerative diseases: their use alone or in combination with lanthionines. [Review].  Free Radical Biology & Medicine. 62:145-56, 2013
    Hubbard C; Benda E; Hardin T; Baxter T; St John E; O'Brien S; Hensley K; Holgado AM.  Lanthionine ketimine ethyl ester partially rescues neurodevelopmental defects in unc-33 (DPYSL2/CRMP2) mutants.  Journal of Neuroscience Research. 91(9):1183-90, 2013
    Nada SE; Tulsulkar J; Raghavan A; Hensley K; Shah ZA.  A derivative of the CRMP2 binding compound lanthionine ketimine provides neuroprotection in a mouse model of cerebral ischemia.  Neurochemistry International. 61(8):1357-63, 2012
    Stansley B; Post J; Hensley K.  A comparative review of cell culture systems for the study of microglial biology in Alzheimer's disease. [Review].  Journal of Neuroinflammation. 9:115, 2012.
    Kadiiska MB; Peddada S; Herbert RA; Basu S; Hensley K; Jones DP; Hatch GE; Mason RP.  Biomarkers of oxidative stress study VI. Endogenous plasma antioxidants fail as useful biomarkers of endotoxin-induced oxidative stress.  Free Radical Biology & Medicine. 81:100-6, 2015
    Hensley K; Denton TT.  Alternative functions of the brain transsulfuration pathway represent an underappreciated aspect of brain redox biochemistry with significant potential for therapeutic engagement. [Review].  Free Radical Biology & Medicine. 78:123-34, 2015
    Hensley K; Gabbita SP; Venkova K; Hristov A; Johnson MF; Eslami P; Harris-White ME.  A derivative of the brain metabolite lanthionine ketimine improves cognition and diminishes pathology in the 3 x Tg-AD mouse model of Alzheimer disease.  Journal of Neuropathology & Experimental Neurology. 72(10):955-69, 2013
    Kadiiska MB; Hatch GE; Nyska A; Jones DP; Hensley K; Stocker R; George MM; Van Thiel DH; Stadler K; Barrett JC; Mason RP.  Biomarkers of Oxidative Stress Study IV: ozone exposure of rats and its effect on antioxidants in plasma and bronchoalveolar lavage fluid.  Free Radical Biology & Medicine. 51(9):1636-42, 2011
   Hensley K; Barnes LL; Christov A; Tangney C; Honer WG; Schneider JA; Bennett DA; Morris MC.  Analysis of postmortem ventricular cerebrospinal fluid from patients with and without dementia indicates association of vitamin E with neuritic plaques and specific measures of cognitive performance.  Journal of Alzheimer's Disease. 24(4):767-74, 2011.
    Floyd RA; Towner RA; He T; Hensley K; Maples KR.  Translational research involving oxidative stress and diseases of aging. [Review].  Free Radical Biology & Medicine. 51(5):931-41, 2011
    Hensley K; Venkova K; Christov A; Gunning W; Park J.  Collapsin response mediator protein-2: an emerging pathologic feature and therapeutic target for neurodisease indications. [Review].  Molecular Neurobiology. 43(3):180-91, 2011
    Kurien BT; Porter A; Dorri Y; Iqbal S; D'Souza A; Singh A; Asfa S; Cartellieri M; Mathias K; Matsumoto H; Bachmann M; Hensley K; Scofield RH.  Degree of modification of Ro60 by the lipid peroxidation by-product 4-hydroxy-2-nonenal may differentially induce Sjogren syndrome or systemic lupus erythematosus in BALB/c mice.  Free Radical Biology & Medicine. 50(10):1222-33, 2011

Last Updated: 6/30/16