UNMC Research Opens New Path to Study Alzheimer's and HIV Link

UNMC researchers have published an article in "Alzheimer's & Dementia: The Journal of the Alzheimer's Association" detailing the creation of an animal model that helps resolve questions about the relationship between HIV and Alzheimer's disease (AD).

The work can serve as a guide for the development of novel therapeutics to halt memory loss antiretroviral drugs have shown strong potential to prevent and slow progression of both HIV and AD. Specific classes of HIV medications suppress brain inflammation and genetic mutations linked to Alzheimer's pathology.

The model demonstrates how the virus that drives the root cause of AD -- the amyloid beta proteins that clump together to form sticky amyloid plaques – initiate a complex chain that, with other disease partners, drives nerve cell injury and cognitive impairments for AD pathology.

Corresponding authors Pravin Yeapuri, PhD, and Howard Gendelman, MD, of the UNMC Department of Pharmacology and Experimental Neuroscience (PEN), say the study is the culmination of decades of work on brain diseases following the creation of UNMC's Center for Neurovirology and Neurodegenerative Disorders in 1997.

Until now, the link between the two disease entities was obscure. But the paper has far-reaching implications, Dr. Yeapuri said, adding "Research has already shown that certain HIV medications (nucleoside reverse transcriptase inhibitors, or NRTIs) may both lower the risk of Alzheimer's disease and significantly reduce brain inflammation."

The UNMC research team, which included Shaurav Bhattarai, PhD, developed an unique animal model to study questions such as:

Does HIV affect the progression of AD, and vice-versa? If so, how?
Could an HIV-AD neurocognitive disorder, driven by different pathologies, converge to cause cognitive dysfunction?
What is the role of aging in HIV-AD? As HIV-infected persons are living into their 70s and longer, does HIV bring added risks of neurodegenerative disease?
Can the findings in this study lead to new therapies that will treat both diseases and if so, how should they be studied and applied?

Dr. Bhattarai noted that people living with HIV have a higher overall risk of developing dementia compared to the general population, though direct evidence specifically linking HIV to a higher prevalence of classic Alzheimer's disease remains unknown.

The animal model overcomes a major barrier in modeling HIV-AD comorbidity, by combining AD-like neurodegeneration with the capacity for human immune reconstitution, said Tsuneya Ikezu, MD, PhD, the Robert D. and Patricia E. Kern Professorship in Neurology and director of the Molecular NeuroTherapeutics Laboratory at the Mayo Clinic. "Developing such a model has been technically challenging, because it requires precise modification and humanization of multiple genetic sequences while preserving physiological, endogenous expression of the relevant AD-associated proteins."

"The HIV-AD disease overlap is driven by persistent and low viral loads and inflammation. The research uncovered specific pathways that are HIV and AD risk factors. Each alone and together lead to brain damage," Dr. Gendelman said. "Characterization of each opens new opportunities for therapies, specifically where antiretroviral therapy or ART can now be used as a treatment for both."

In the study, nerve cells were found most vulnerable to injury despite not being directly HIV-1 infected. This finding highlighted how HIV and AD in tandem affect the nervous system in aged people.

"Specific ART component drugs can block that inflammation that can trigger both diseases," Dr. Gendelman said.

"Studies show older adults with HIV experience higher rates of overall dementia (around 2.5%) compared to uninfected persons (around 1.3%). As HIV-infected persons live longer lives, they become vulnerable to age-related conditions like Alzheimer's disease and vascular dementia, which are aggravated by chronic inflammation in the brain."

Collaborators included Emma Foster, Rana Kadry, Yaman Lu, Mohit Kumar and Syed Qasim together with Larisa Poluektova, MD, PhD, Santhi Gorantla, PhD, and R. Lee Mosley, PhD, of the PEN department at the University of Nebraska Medical Center and Amrita Mitra, PhD, and Harsh Pathak, PhD, of the University of Kansas Medical Center.