Kristian Doyle

Kristian Doyle

Associate Professor, Immunobiology
Associate Professor, Neurology
Associate Professor, Neurosurgery
Associate Professor, Psychology
Associate Professor, Neuroscience - GIDP
Member of the Graduate Faculty
Research Scientist
Associate Professor, BIO5 Institute
Primary Department
Department Affiliations
(520) 626-7013

Work Summary

Approximately 795,000 Americans suffer a stroke each year, and 400,000 will experience long-term disability. The number of stroke survivors in the population is expected to double by 2025. Currently, treatments for stroke patients are limited to tissue plasminogen activator (TPA), but its use is limited to the first few hours after stroke. Therefore, the goal of our research is to develop new therapeutics that can promote repair and recovery in this rapidly growing population.

Research Interest

The Doyle lab investigates the role of the immune system in causing dementia after stroke. Up to 30% of stroke patients develop dementia in the months and years after their stroke and we are testing the hypothesis that in some patients this is due to a chronic inflammatory response that persists at the site of the stroke infarct. We suspect that in the weeks, months and possibly years after stroke, neurotoxic inflammatory mediators, including T cells, cytokines and antibodies, leak out of the stroke infarct and cause bystander damage to the surrounding tissue, which then both impairs recovery, and in some instances leads to cognitive decline. In support of this hypothesis we have data that demonstrates that inflammation persists for months at the site of the infarct after stroke, and that a single stroke can directly lead to the development of immune-mediated delayed cognitive deficits. We are currently in the process of targeting different components of the prolonged inflammatory response to stroke to determine if post stroke dementia can be treated by selectively ablating individual immune mediators such as B lymphocytes, T lymphocytes, and CCR2. Keywords: Neuroinflammation, stroke, dementia, Alzheimer's disease


Bartlett, M. J., Flores, A. J., Dollish, H. K., Farrell, D. C., Parent, K. L., Besselsen, D. G., Heien, M. L., Doyle, K., Cowen, S. L., Steece-Collier, K., Sherman, S. J., & Falk, T. (2017). Neuroplastic mechanism of sub-anesthetic ketamine treatment to reduce development of L-DOPA-induced dyskinesia. Science Translational Medicine.
BIO5 Collaborators
David G Besselsen, Kristian Doyle
Branca, C., Ferreira, E., Nguyen, T. V., Doyle, K., Caccamo, A., & Oddo, S. (2017). Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer's disease. Human molecular genetics, 26(24), 4823-4835.

Aging is the major risk factor for several neurodegenerative diseases, including Alzheimer's disease (AD). However, the mechanisms by which aging contributes to neurodegeneration remain elusive. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor that regulates expression of a vast number of genes by binding to the antioxidant response element. Nrf2 levels decrease as a function of age, and reduced Nrf2 levels have been reported in postmortem human brains and animal models of AD. Nevertheless, it is still unknown whether Nrf2 plays a role in the cognitive deficits associated with AD. To address this question, we used a genetic approach to remove the Nrf2 gene from APP/PS1 mice, a widely used animal model of AD. We found that the lack of Nrf2 significantly exacerbates cognitive deficits in APP/PS1, without altering gross motor function. Specifically, we found an exacerbation of deficits in spatial learning and memory, as well as in working and associative memory. Different brain regions control these behavioral tests, indicating that the lack of Nrf2 has a global effect on brain function. The changes in cognition were linked to an increase in Aβ and interferon-gamma (IFNγ) levels, and microgliosis. The changes in IFNγ levels are noteworthy as previously published evidence indicates that IFNγ can increase microglia activation and induce Aβ production. Our data suggest a clear link between Nrf2 and AD-mediated cognitive decline and further strengthen the connection between Nrf2 and AD.

Danilo, C. A., Constantopoulos, E., McKee, L. A., Chen, H., Regan, J. A., Lipovka, Y., Lahtinen, S., Stenman, L. K., Nguyen, T. V., Doyle, K. P., Slepian, M. J., Khalpey, Z. I., & Konhilas, J. P. (2017). Bifidobacterium animalis subsp. lactis 420 mitigates the pathological impact of myocardial infarction in the mouse. Beneficial microbes, 8(2), 257-269.

There is a growing appreciation that our microbial environment in the gut plays a critical role in the maintenance of health and the pathogenesis of disease. Probiotic, beneficial gut microbes, administration can directly attenuate cardiac injury and post-myocardial infarction (MI) remodelling, yet the mechanisms of cardioprotection are unknown. We hypothesised that administration of Bifidobacterium animalis subsp. lactis 420 (B420), a probiotic with known anti-inflammatory properties, to mice will mitigate the pathological impact of MI, and that anti-inflammatory T regulatory (Treg) immune cells are necessary to impart protection against MI as a result of B420 administration. Wild-type male mice were administered B420, saline or Lactobacillus salivarius 33 (Ls-33) by gavage daily for 14 or 35 days, and underwent ischemia/reperfusion (I/R). Pretreatment with B420 for 10 or 28 days attenuated cardiac injury from I/R and reduced levels of inflammatory markers. Depletion of Treg cells by administration of anti-CD25 monoclonal antibodies eliminated B420-mediated cardio-protection. Further cytokine analysis revealed a shift from a pro-inflammatory to an anti-inflammatory environment in the probiotic treated post-MI hearts compared to controls. To summarise, B420 administration mitigates the pathological impact of MI. Next, we show that Treg immune cells are necessary to mediate B420-mediated protection against MI. Finally, we identify putative cellular, epigenetic and/or post-translational mechanisms of B420-mediated protection against MI.

Meller, R., Stevens, S. L., Minami, M., Cameron, J. A., King, S., Rosenzweig, H., Doyle, K., Lessov, N. S., Simon, R. P., & Stenzel-Poore, M. P. (2005). Neuroprotection by osteopontin in stroke. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 25(2), 217-25.

Osteopontin (OPN) is a secreted extracellular phosphoprotein involved in diverse biologic functions, including inflammation, cell migration, and antiapoptotic processes. Here we investigate the neuroprotective potential of OPN to reduce cell death using both in vitro and in vivo models of ischemia. We show that incubation of cortical neuron cultures with OPN protects against cell death from oxygen and glucose deprivation. The effect of OPN depends on the Arg-Gly-Asp (RGD)-containing motif as the protective effect of OPN in vitro was blocked by an RGD-containing hexapeptide, which prevents integrin receptors binding to their ligands. Osteopontin treatment of cortical neuron cultures caused an increase in Akt and p42/p44 MAPK phosphorylation, which is consistent with OPN-inducing neuroprotection via the activation of these protein kinases. Indeed, the protective effect of OPN was reduced by inhibiting the activation of Akt and p42/p44 MAPK using LY294002 and U0126, respectively. The protective effect of OPN was also blocked by the protein synthesis inhibitor cycloheximide, suggesting that the neuroprotective effect of OPN required new protein synthesis. Finally, intracerebral ventricular administration of OPN caused a marked reduction in infarct size after transient middle cerebral artery occlusion in a murine stroke model. These data suggest that OPN is a potent neuroprotectant against ischemic injury.

Doyle, K. P., Yang, T., Lessov, N. S., Ciesielski, T. M., Stevens, S. L., Simon, R. P., King, J. S., & Stenzel-Poore, M. P. (2008). Nasal administration of osteopontin peptide mimetics confers neuroprotection in stroke. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 28(6), 1235-48.

Osteopontin (OPN), a large secreted glycoprotein with an arginine, glycine, aspartate (RGD) motif, can bind and signal through cellular integrin receptors. We have shown previously that OPN enhances neuronal survival in the setting of ischemia. Here, we sought to increase the neuroprotective potency of OPN and improve the method of delivery with the goal of identifying a treatment for stroke in humans. We show that thrombin cleavage of OPN improves its ability to ligate integrin receptors and its neuroprotective capacity in models of ischemia. Thrombin-cleaved OPN is a twofold more effective neuroprotectant than the untreated molecule. We also tested whether OPN could be administered intranasally and found that it is efficiently targeted to the brain via intranasal delivery. Furthermore, intranasal administration of thrombin-treated OPN confers protection against ischemic brain injury. Osteopontin mimetics based on the peptide sequences located either N or C terminal to the thrombin cleavage site were generated and tested in models of ischemia. Treatment with successively shorter N-terminal peptides and a phosphorylated C-terminal peptide provided significant neuroprotection against ischemic injury. These findings show that OPN mimetics offer promise for development into new drugs for the treatment of stroke.