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 and 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. 

1. 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.
2. 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.

Faculty Director of the Bachelor of Science, Pharmacology and Toxicology Program

Background: Dr. Johnson received a BS in Biology (1984) and MS in Pharmacology (1986) from the University of Minnesota-Duluth, and a PhD in Environmental Toxicology (1992) from the University of Wisconsin. He did postdoctoral training in the Department of Pharmacology at the University of Washington and spent four years as an assistant professor at the University of Kansas Medical Center before joining the University of Wisconsin School of Pharmacy faculty in 1999. Dr. Johnson is the Director of the Pharmacology and Toxicology BS program. He is also a member of the Waisman Center, Center for Neuroscience, Neuroscience Training Program, Cellular and Molecular Biology Training Program, MD/PhD Training Program, Molecular and Environmental Toxicology Training Program, and Molecular and Cellular Pharmacology Training Program.

Professional Interests: Transcriptional control of neuroprotective genes and prevention of neurodegeneration in Parkinson's, Alzheimer's, Huntington's and neuromuscular disease.  A focus on dysfunctional proteostasis in disease progression and viral-mediated delivery of protective genes to the brain.

Education:

• BS 1984 Biology - University of Minnesota-Duluth
• MS 1986 Pharmacology - University of Minnesota-Duluth
• PhD 1992 Environ. Toxicology - University of Wisconsin
• Postdoctoral Training 1992-95 Neuroscience - University of Washington

Contribution to Science

1.  Establishing that Nrf2 activation in astrocytes can be neuroprotective in vitro.  We established that astrocytic activation of Nrf2 conferred protection to co-cultured cortical, motor, and dopaminergic neurons.

Lee, J.M., Calkins, M.J., Chan, K., Kan, Y.W. and J.A. Johnson (2003). Identification of the NF-E2-related factor 2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J Biol. Chem. 278:12029-38.

Lee, J.M., Shih, A.Y., Murphy, T.H. and J.A. Johnson (2003). NF-E2-related factor 2 mediates neuroprotection against mitochondrial complex I inhibitors and increased concentrations of intracellular calcium in primary cortical neurons. J. Biol. Chem. 278 (39): 37948-56.

Kraft, A.D., Johnson, D.A. and J.A. Johnson (2004). Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult. J Neurosci. 24(5):1101-12.

Hoang TT, Johnson DA, Raines RT, Johnson JA (2019). Angiogenin activates the astrocytic Nrf2/antioxidant-response element pathway and thereby protects murine neurons from oxidative stress. J Biol Chem. 294(41):15095-15103.

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. PMID: 38241649 #Corresponding authors.

2.  Translation of the in vitro astrocyte data to in vivo models of neurodegenerative diseases.  To translate the finding in 1, transgenic mice were engineered to selectively overexpress and/or have increased Nrf2 activation in response to brain injury.  These GFAP-Nrf2 mice have clearly established Nrf2 as a viable therapeutic target for the treatment of neurodegenerative diseases.  GFAP-Nrf2 mice have increased resistance to mitochondrial neurotoxicants, as well as delayed the onset and/or increased the lifespan mouse models of amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease.

Vargas, M.R., Johnson, D.A., Sirkis, D.W., Messing, A. and J.A. Johnson (2008). Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J. Neurosci. 28(50):13574-81.

Chen PC, Vargas MR, Pani AK, Smeyne RJ, Johnson DA, Kan YW, and J.A. Johnson (2009). Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte. Proc Natl Acad Sci U S A. 106(8):2933-8.

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.  Neurosci. 32(49): 17775-17787. 

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.

Publications - https://scholar.google.com/citations?user=n76H-P0AAAAJ hl=en