Dr. James G. McLarnon,
B.Sc (Physics); M. Sc (Nuclear Physics): University of Alberta
Professor Emeriti – Anesthesiology, Pharmacology and Therapeutics
|Department of Anesthesiology, Pharmacology and Therapeutics|
A prominent theme of my recent research studies involves the roles and mechanisms by which microglia, resident immune cells of brain, mediate inflammatory responses in Alzheimer’s disease (AD) and in brain tumors. Overall, my laboratory has published in excess of 120 papers using a spectrum of experimental methods applied in vitro in cultured glial and neuronal cells and in vivo in animal models of disease.
A specific focus of recent work concerns how interactions between microglia and brain vasculature sustain and amplify chronic inflammation in AD. In particular, considerable evidence suggests vascular dysfunction and reduced cerebral blood flow are manifest as an early event in AD. Data from my lab, including use of an animal model of AD and use of brain tissue from AD patients (see papers listed below relevant to AD), suggest microglial inflammatory responses to amyloid-β peptide in AD brain lead to leakiness of the blood-brain barrier (BBB). Increased permeability of BBB allows infiltration of plasma proteins, such as fibrinogen, into brain parenchyma, sustaining microglial activation and brain inflammation.
Microglia responses in chronic inflammation include secretion of a spectrum of pro-inflammatory factors including chemokines, cytokines, reactive oxygen species and proteinases. Two particular factors are vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF-α) which serve as potent stimuli for angiogenesis, the growth of new, but morphologically abnormal, blood vessels. A hypothesis is that pathogenic angiogenic activity is a component of vascular dysfunction and chronic inflammation in AD brain. My studies also implicate microglial angiogenic responses in cancer. Results from in vivo and in vitro work (see papers listed below relevant to brain tumors) indicate that growth of brain tumors involve signals from tumor cells to mobilize and activate microglia in areas of tumor boundaries to produce VEGF and TNF-α fueling angiogenesis.
In summary, an aging AD brain exhibits chronic microglial pro-inflammatory reactivity in an environment of increased amyloid-β deposition in blood vessel walls and brain parenchyma, reduced cerebral blood flow through occluded vessels and leaky BBB and abnormalities such as formation of tau microtubules. Chronic inflammation is suggested as a critical contributing factor to impaired synaptic and neuronal cortical and hippocampal function in AD brain.
My studies suggest that a combination “cocktail” approach to block specific microglial inflammatory pathways as a strategy to markedly slow the progression of cognitive and memory impairment in AD. Work from my lab has identified four particular compounds which have shown utility in modulation of microglial responses and neuroprotection. It is predicted that in assemblage, the compounds will show enhanced anti-inflammatory efficacy. Importantly, all compounds exhibit permeability through BBB and low levels of cellular toxicity. A critical initial step is to test the compounds in an animal model of AD.
A second research approach is to examine pharmacological modulation of microglial interactions with components of BBB and angiogenic processes as a strategy to reduce chronic inflammation in AD. The inhibition of microglial-induced angiogenesis would also be expected to have utility as an approach to slow progression of brain tumors.
Selected Publications (relevance to Alzheimer’s disease):
 Ryu JK and McLarnon JG (2008) Thalidomide inhibition of perturbed vasculature and glial-derived tumor necrosis factor-α in an animal model of inflamed Alzheimer’s disease brain. Neurobiol Dis 29; 254-266.
 McLarnon JG, Ryu JK (2008) Relevance of Aβ1-42 intrahippocampal injection as an animal model of inflamed Alzheimer’s disease brain. Curr Alz Res 5; 475-480.
 Ryu JK and McLarnon, JG (2009) A leaky blood-brain barrier, fibrinogen infiltration and microglial reactivity in inflamed Alzheimer’s disease brain. J Cell Mol Med 13; 2911-2925.
 Ryu JK, Cho T, Choi HB, Wang YT and McLarnon JG (2009) Microglial VEGF receptor response is an integral chemotactic component in Alzheimer’s disease pathology. J Neurosci 29; 3-13.
 Jantaratnotai N, Schwab C, Ryu JK, McGeer PL, McLarnon JG (2010) Converging perturbed microvasculature and microglial clusters characterize Alzheimer disease brain. Curr Alz Res 7, 625-636.
 Hashioka S, McLarnon JG, Ryu JK, Youssef AM, Abd-El-Aziz A, Neeland EG, Klegeris A (2011) Pyrazole compound 2-MBAPA as a novel inhibitor of microglial activation and neurotoxicity in vitro and in vivo. J Alz Dis 27; 531-541.
 Jantaratnotai N, Ryu JK, Schwab C, McGeer PL, McLarnon JG (2011) Comparison of vascular perturbations in an Aβ-injected animal model and in AD brain. Int J Alz Dis vol 2011.
 Ryu JK, Little JP, Klegeris A, Jantaratnotai N and Mclarnon JG (2013) Actions of the anti-angiogenic compound angiostatin in an animal model of Alzheimer’s disease. Curr Alz Res 10; 252-260.
 Jantaratnotai N, Ling A, Cheng J, Schwab C, McGeer PL, McLarnon JG (2013) Upregulation and expression patterns of the angiogenic transcription factor Ets-1 in Alzheimer’s disease brain. J Alz Dis 37; 367-377.
 Ryu JK, Choi HB, Jantaratnotai N, McLarnon JG (2015) Pharmacological antagonism of interleukin-8 receptor CXCR2 inhibits inflammatory reactivity and is neuroprotective in an animal model of Alzheimer’s disease. J Neuroinflamm 12: 144
Selected Publications (relevance to brain tumors):
 Wei W, Ryu JK, Choi HB, McLarnon (2008) Expression and function of the P2X7 receptor in rat C6 glioma cells. Cancer Lett 260; 79-87.
 Jantaratnotai N, Choi HB, McLarnon JG (2009) ATP stimulates chemokine production via a store-operated calcium entry pathway in C6 glioma cells. BMC Cancer 9; 442
 Ryu JK, Jantaratnotai N, Serrano-Perez MC, McGeer PL, McLarnon JG (2010) Block of purinergic P2X7R inhibits tumor growth in a C6 brain tumor animal model. J Neuropathol Exp Neurol 70; 13-22.
 McLarnon JG (2017) Roles of purinergic P2X7 receptor in glioma and microglia in brain tumors. Cancer Lett 402; 93-99.