Brain’s Immune Function

There is no doubt that the clinical manifestations of dementia are due, in part, to pathologies associated with neurons: plaques, tangles, Lewy bodies, TDP-43 inclusions, etc. However, an emerging body of evidence suggests that alterations in the brain’s immune function, or neuroinflammation, may play an integral if not more robust role than neuronal pathologies alone in disease progression. Indeed, recent findings support that inflammation has causal roles in the initiation, progression, and maintenance of a variety of neurodegenerative diseases linked with dementia. Increasing evidence regarding the effect of neuroinflammation upon disease pathogenesis points toward the idea that the clinical syndromes of dementia may not be restricted to the neuronal compartment alone, but rather could be the result of a dysfunctional immune response in the brain.

Astrocytes and Microglia

Two of the key mediators believed to have the most robust regulation of the brain’s immune response are cells called astrocytes and microglia (pictured above). These two cell populations cover the entire brain and combined outnumber the total number of neurons. Both astrocytes and microglia are intrinsically involved in maintaining homeostasis, whether it be during development or during our adulthood. Both of these cell populations in the healthy brain provide critical support to keep neurons functioning properly. However, even prior to the accumulation of neuronal pathologies in disease, both astrocytes and microglia become reactive, favoring a ‘pro-inflammatory’ bias in lieu of maintaining homeostatic functions. Understanding what drives these highly potent cells toward this reactive and detrimental bias will pave the way for immune-focused therapies to prevent dementia.

Researchers at Sanders-Brown Center on Aging have a long history of examining disrupted immune functions that may underly the progression of dementia syndromes.

Ongoing work in these areas is highlighted below:

Hereditary risk factors are the predominant cause of Alzheimer’s disease.  Our lab is working to define the mechanisms underlying these factors.  The genes underlying these risk factors are generally expressed in microglia, focusing our efforts on this cell type in particular and inflammation in general.  Our work uses human brain samples to investigate how genetics affects gene expression, in vitro models to investigate these actions at the cellular level, and murine models to investigate the actions of these factors on Alzheimer’s related neuropathology in vivo.  Our long-term goal is to identify pharmacologic agents that target these mechanisms and thereby reduce Alzheimer’s disease risk.

Inflammation and microglia remain essential for protein clearance and quality control of tissue maintenance but appear to decline during age-related diseases. Recent reports indicate that arginine, arginase, and products of arginine metabolism known as polyamines are required for continual efferocytosis (‘to take to the grave’, ‘to bury’) or engulfment by microglia. Our current work has uncovered a critical link for arginine metabolism in the regulation of microglial function. We have identified several novel inhibitors of this arginine-mediated response that regulate phagocytosis. Ultimately, our goal is to identify unique therapeutic targets of arginine signaling that improve impaired microglial function with respect to neuroinflammation, Alzheimer’s disease, and protein-folding disorders but show minimal changes to other systems.

The occurrence of increased reactivity of astrocytes and microglia prior to the deposition of neuronal pathologies such as plaques and tangles, may indicate that these cells and their responses are some of the first mechanisms to target as a preventative therapeutic strategy against clinical dementia syndromes. Work in our lab is aimed at understanding why and how astrocytes and microglia acquire a ‘preference’ for utilizing specific transcription factors that promote dysfunctional neuroinflammation in the brain. Is their preference due purely to extrinsic signaling upon each cell, or have these cells dysfunctionally acquired modifications internally that bias their genetic repertoire? Further, how do these modifications alter crosstalk signaling mechanisms between astrocytes and microglia that may drive disruptive feed-forward responses? Overall, our long-term goal is to determine whether exploiting these regulatory factors through either inhibition or agonism represents translatable therapeutic strategies to prevent neurodegenerative conditions.

We have developed novel classes of brain-penetrant, small molecule inhibitors of dysregulated neuroinflammation. Our compounds are selective suppressors of injury- and disease-induced proinflammatory cytokine overproduction associated with destructive glia inflammation/ synaptic dysfunction cycles. These drug candidates are efficacious in animal models of multiple CNS disorders where neuroinflammation contributes to disease progression, including Alzheimer’s disease and related dementias, hemorrhagic stroke, traumatic brain injury, and seizures. Three of our compounds have entered or completed phase 1 safety trials in human volunteers.

Steve Estus

(859) 218-3858 (office)

Daniel Lee

(859) 323-6506 (office)

Dan Lee Lab

Linda Van Eldik

(859) 257-5566 (office)
(859) 323-2866 (fax)

Josh Morganti