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Pulse - Summer/Fall 2018 Natural Defenses: Protecting the Brain From Degenerative Disease

Olimpia Meucci, MD, PhD

When Olimpia Meucci first began researching the impact of neuroinflammation on the neurological complications of HIV/AIDS, it was at the height of the global panic about the emerging health threat. "HIV was a major medical problem. People recognized that, in addition to compromising the immune system, the disease caused neurological deficits," Meucci says. "However, because severe neurological deficits typically occurred when the disease had progressed to a point where there was little to be done for the patient, no one was looking closely at how to mitigate these issues. At the time, most clinical and research efforts were directed at halting viral replication and infection."

Today, although HIV-infected patients have long benefited from antiretroviral therapies, there is still no treatment for the neurocognitive disorders associated with HIV/AIDS. Meucci is hoping to change that. Now professor and chair of Drexel's Department of Pharmacology & Physiology and director of the Center for Neuroimmunology & CNS Therapeutics, Institute of Molecular Medicine & Infectious Disease, she just received funding from the NIH for the 16th year in a row, supporting her work around neuroHIV. Ongoing studies in her lab primarily focus on neuroprotective pathways and the role of substance abuse and aging in HIV-associated cognitive decline.

After earning her medical and PhD degrees at the University of Naples in her native Italy, Meucci came to the United States for further training. With fellowship awards from the Italian Institute of Public Health and the Association of Neurological Research, she pursued AIDS research at the University of Chicago. Among her most profound discoveries was that chemokine receptors play key roles in HIV-induced neuronal damage and control essential neuronal and glial functions.

Meucci brought her work to the College of Medicine in 2000. She has continued to build on those early investigations, looking at mechanisms whereby chemokines regulate neuronal survival and neurotransmission, with the goal of finding ways to guard against the destructive effects of HIV in the brain. The research also extends beyond HIV-associated neurocognitive disorders (HAND) — with implications for other diseases such as Alzheimer's and schizophrenia, which show similar decreases in dendritic spine density. (Dendritic spines — tiny protrusions from a neuron's dendrite — receive input from synapses and are critical for signaling and memory.)

"If we can better characterize the roles of chemokines in the central nervous system, we can develop therapies that promote their neuroprotective abilities and reduce or reverse neuronal deficits," she says. "I would like to find a path to get adjuvant HAND treatments to the clinic, whether it's a way to slow down the functional damage or reduce the neurocognitive impairments as people age."

"Though we think of HIV/AIDS almost as a chronic disease now, these disorders still demand a treatment."

In her newest NIH-funded work, Meucci is also studying how factors such as drug abuse — specifically opiate use disorder — may hasten the onset of neurological symptoms by contributing to the destruction of dendritic spines and excitotoxicity. "We believe opiates could alter the normal function of select chemokine receptors in a way that contributes to overall damage," she says.

Multiple Models

In the lab, Meucci's team deploys in vitro, ex vivo, and in vivo models to examine the disease's impact on cognitive function. "In the animal models we can reproduce aspects of the disease at the cellular and system level, and determine how to promote pathways that are neuroprotective. Notably, we are able to characterize the change in [dendritic] spines, molecular mediators and cognitive performance in the same animal — which allows us to draw compelling conclusions about mechanistic details, and helps identify potential therapeutic targets. Also, we have access through the NIH to unique brain repositories that provide ways to validate these cellular targets in human specimens, taking us closer to the human pathology."

An upcoming paper will present Meucci's recent findings on changes in complex cognitive behavior in animal models as a result of specific molecular alterations induced by HIV neurotoxins. "This could be a valuable preclinical model to test candidate drugs against HAND and other neuroinflammatory disorders, which would be a major advantage in the field. What has always interested me is the intersection of neuroscience, immunology and pharmacology — this work sits right at the crossroads."

HIV/AIDS is not the global pandemic people once feared. Therapies have allowed HIV/AIDS patients to live nearly normal life spans, and the clinical manifestations of the disease have changed. Still, about 40 million people worldwide are living with HIV, and as Meucci points out, HAND can deeply impact patients' quality of life, everyday functioning and overall survival.

"You can see cognitive dysfunction, such as loss of attention or loss of memory or the ability to accomplish complex tasks, in treated patients," she says. "Furthermore, the virus gets into the brain very early on, which creates major obstacles to virus eradication and effective treatment. Last but not least, as treated patients are getting older, comorbidities, such as cardiovascular or renal disorders and cancer, present unique challenges," she continues. "Though we think of HIV/AIDS almost as a chronic disease now, these disorders still demand a treatment."

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