Jeffrey Johnson, PhD

Position title: Vilas Distinguished Achievement Professor, Pharmacy

PhD, University of Wisconsin

Contact Information

School of Pharmacy
University of Wisconsin
777 Highland Ave.
Madison, WI 53705
608.262.2893
jeffrey.johnson@wisc.edu
The Johnson Lab

Research Statement

Alzheimer’s Disease (AD) is the most common neurodegenerative disease, impacting roughly 6.7 million Americans currently and up to 13.8 million by 2060 without disease-modifying therapeutics. The greatest risk factor for developing AD is age. AD and aging are associated with increased oxidative stress, mitochondrial dysfunction, inflammation, and protein aggregation, as well as impaired proteostasis. The laboratories overall work has focused on the Keap1 (Kelch-like ECH-associating protein 1)/Nrf2 (nuclear factor erythroid 2-related factor 2) pathway because activation of this pathway mitigates those AD associated mechanisms and thus poses an opportunity for novel therapeutic strategies. The protein-protein interaction (PPI) between Keap1 and Nrf2 sequesters Nrf2 in the cytoplasm. Disruption of this PPI allows for accumulation and nuclear translocation of Nrf2 where it binds to the antioxidant response element (ARE). Nrf2 binding to the ARE transcriptionally drives expression of several detoxifying and antioxidant genes. This leads to increased resistance to mitochondrial dysfunction, oxidative stress, and inflammation. More recently, genes involved in maintaining and/or enhancing proteostasis through the UPS (ubiquitin proteasome system) and autophagy have been found to be Nrf2-dependent. Previous work in the laboratory found that Nrf2 activation/overexpression in astrocytes confers protection to neighboring neurons in vitro and in vivo. More recently, in collaboration with two other groups at the University of Edinburgh, we examined the impact of astrocytic Nrf2 activation in two mouse models of AD (APP/PS1 and MAPTP301S). Transgenic mice using the glial fibrillary acidic protein (GFAP) to drive Nrf2 expression in astrocytes (GFAP-Nrf2 mice) were crossed with the two AD models¹. In both cases, there was a significant attenuation of pathology with reduced tau phosphorylation and neuronal loss in MAPTP301S mice, as well as a 70-80% reduction in amyloid-beta (Aβ) and plaque load in APP/PS1 mice. These data clearly demonstrate the high therapeutic potential for Nrf2-activating compounds/biologics in AD. Current projects include: 1) determining the neuroprotective mechanisms mediated by astrocytic Nrf2 activation; 2) the role of Nrf2 in microglial activation; 3) viral-mediated delivery of Nrf2 to neurons and astrocytes; and 4) based on a recent publication², the development of Keap1/Nrf2 PPI disruptors for activation of the Nrf2 pathway.

Jiwaji Z*, Tiwari SS*, Avilés-Reyes RX*, Hooley M*, Hampton D, Torvell M, Johnson DA, McQueen J, Baxter P, Sabari-Sankar K, Qiu J, He X, Fowler J, Febery J, Gregory J, Rose J, Tulloch J, Loan J, Story D, McDade K, Smith AM, Greer P, Ball M, Kind PC, Matthews PM, Smith C, Dando O, Spires-Jones TL, Johnson JA#, Chandran S#, Hardingham GE#. (2022). Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology. Nat Commun. 2022 Jan 10;13(1):135.*Equal contribution and #Corresponding authors.
Carrow, KP, Hamilton, HL, Hopps, MP, Li, Y, Qiao, B, Payne, NC, Thompson, MP, Zhang, X, Magassa, A, Fattah, M, Agarwal, S, Vincent, MP, Buyanova, M, Bertin, PA, Mazitschek, R, Olvera de la Cruz, M, Johnson, DA#, Johnson, JA#, Gianneschi, NC#. (2024) Inhibiting the Keap1/Nrf2 Protein-Protein Interaction with Protein-Like Polymers. Adv Mater. 2024 Jan 19; e2311467. #Corresponding authors.

Selected Publications

PubMed

Carrow, K. P., Hamilton, H. L., Hopps, M. P., Li, Y., Qiao, B., Payne, N. C., Thompson, M. P., Zhang, X., Magassa, A., Fattah, M., Agarwal, S., Vincent, M. P., Buyanova, M., Bertin, P. A., Mazitschek, R., Olvera de la Cruz, M., Johnson, D. A., Johnson, J. A., & Gianneschi, N. C. (2024). Inhibiting the Keap1/Nrf2 Protein-Protein Interaction with Protein-Like Polymers. Advanced materials (Deerfield Beach, Fla.), 36(21), e2311467. https://doi.org/10.1002/adma.202311467
Molina-Gonzalez, I., Holloway, R. K., Jiwaji, Z., Dando, O., Kent, S. A., Emelianova, K., Lloyd, A. F., Forbes, L. H., Mahmood, A., Skripuletz, T., Gudi, V., Febery, J. A., Johnson, J. A., Fowler, J. H., Kuhlmann, T., Williams, A., Chandran, S., Stangel, M., Howden, A. J. M., Hardingham, G. E., … Miron, V. E. (2023). Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration. Nature communications, 14(1), 3372. https://doi.org/10.1038/s41467-023-39046-8
Jiwaji, Z., Tiwari, S. S., Avilés-Reyes, R. X., Hooley, M., Hampton, D., Torvell, M., Johnson, D. A., McQueen, J., Baxter, P., Sabari-Sankar, K., Qiu, J., He, X., Fowler, J., Febery, J., Gregory, J., Rose, J., Tulloch, J., Loan, J., Story, D., McDade, K., … Hardingham, G. E. (2022). Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology. Nature communications, 13(1), 135. https://doi.org/10.1038/s41467-021-27702-w
Killoy KM, Harlan BA, Pehar M, Helke KL, Johnson JA, Vargas MR. (2018). Decreased glutathione levels cause overt motor neuron degeneration in hSOD1^WT over-expressing mice. Experimental Neurology, 302:129-135. doi: 10.1016/j.expneurol.2018.01.004.
Lee LY, Harberg C, Matkowskyj KA, Cook S, Roenneburg D, Werner S, Johnson DA, Johnson JA, Foley DP. (2016) Cell-specific overactivation of nuclear erythroid 2 p45-related factor 2-mediated gene expression in myeloid cells decreases hepatic ischemia/reperfusion injury. Liver Transplantation. 22(8):1115-28. doi: 10.1002/lt.24473.
Joshi G, Gan KA, Johnson DA, Johnson JA. (2015) Increased Alzheimer’s disease-like pathology in the APP/ PS1ΔE9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiology of Aging. 36(2):664-79. doi: 10.1016/j.neurobiolaging.2014.09.004.
Johnson DA, Johnson JA. (2015) Nrf2–a therapeutic target for the treatment of neurodegenerative diseases. Free Radical Biology & Medicine. 88(Pt B):253-67. doi: 10.1016/j.freeradbiomed.2015.07.147.
Cho PY, Joshi G, Boersma MD, Johnson JA, Murphy RM. (2015) A Cyclic Peptide Mimic of the β-Amyloid Binding Domain on Transthyretin. ACS Chemical Neuroscience. 20;6(5):778-89. doi: 10.1021/cn500272a.
Cho PY, Joshi G, Johnson JA, Murphy RM. (2014) Transthyretin-derived peptides as β-amyloid inhibitors. ACS Chemical Neuroscience. ACS Chem Neurosci. 2014 Jul 16;5(7):542-51. doi: 10.1021/cn500014u.
Gan L, Johnson JA. (2014) Oxidative damage and the Nrf2-ARE pathway in neurodegenerative diseases. Biochimica et Biophysica Acta. 1842(8):1208-18. doi: 10.1016/j.bbadis.2013.12.011.
Vargas MR, Burton NC, Kutzke J, Gan L, Johnson DA, Schäfer M, Werner S, Johnson JA. (2013) Absence of Nrf2 or its selective overexpression in neurons and muscle does not affect survival in ALS-linked mutant hSOD1 mouse models. PLoS One. 8(2):e56625.
Zhang, L., Johnson, D., & Johnson, J. A. (2013). Deletion of Nrf2 impairs functional recovery, reduces clearance of myelin debris and decreases axonal remyelination after peripheral nerve injury. Neurobiology of disease, 54, 329–338. https://doi.org/10.1016/j.nbd.2013.01.003
Dowell, J. A., & Johnson, J. A. (2013). Mechanisms of Nrf2 protection in astrocytes as identified by quantitative proteomics and siRNA screening. PloS one, 8(7), e70163. https://doi.org/10.1371/journal.pone.0070163
Gan L, Vargas MR, Johnson DA, Johnson JA. (2012) Astrocyte-specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS in the alpha-synuclein mutant (A53T) mouse model. J Neurosci. 5;32(49):17775-87.
Williamson TP, Johnson DA, Johnson JA. (2012) Activation of the Nrf2-ARE pathway by siRNA knockdown of Keap1 reduces oxidative stress and provides partial protection from MPTP-mediated neurotoxicity. Neurotoxicology. Feb 9;33(3):272-279.
Williamson TP, Amirahmadi S, Joshi G, Kaludov NK, Martinov MN, Johnson DA, Johnson JA. (2012) Discovery of potent, novel Nrf2 inducers via quantum modeling, virtual screening, and in vitro experimental validation. Chemical Biology & Drug Design. Dec;80(6):810-20.