Dementia from HIV May Mirror Elderly Cognitive Problems
July 11, 2012 – Cognitive problems may develop in HIV patients because the virus stops the brain from producing a protein providing “food” for brain neurons – a lack that may also account for elderly dementia, say researchers at Georgetown University Medical Center (GUMC).
The researchers believe their findings may explain why HIV patients using antiretroviral therapy who show no signs of AIDS, develop serious depression as well as profound problems with memory, learning and motor function.
Published in the July 11 issue of the Journal of Neuroscience, the findings may ultimately lead to a therapeutic solution for HIV and elderly patients who suffer brain ailments that appear to develop through the same pathway.
Young Brains Acting Old
“We believe we have discovered a general mechanism of neuronal decline that even explains what happens in some elderly folks,” says the study’s lead investigator, Italo Mocchetti, professor and vice chair of the department of neuroscience at GUMC. “The HIV-infected patients who develop this syndrome are usually quite young, but their brains act old.”
The research team found that even though HIV does not infect neurons, it tries to stop the brain from producing mature brain derived neurotrophic factor (mature BDNF), which Mocchetti says acts as “food” for brain neurons.
Reduced mature BDNF results in the shortening of the axons and their branches that neurons use to connect to each other.
When they lose this communication, the neurons die.
Years of Research
Mocchetti says HIV-associated dementia occurs in 2 to 3 percent of HIV-infected patients using retroviral therapies who appear otherwise healthy, and in 30 percent of HIV-positive patients who are not on medication.
He believes HIV stops production of mature BDNF because that protein interferes with the ability of the virus to attack other brain cells.
The study is the product of years of work. It began when Mocchetti and his colleagues received a grant from the National Institutes on Drug Abuse to determine whether there was a connection between the use of cocaine and morphine and dementia. (A substantial number of HIV-positive patients are intravenous drugs users.)
They found the virus was responsible for the dementia, not the drugs, and set out to discover how the virus was altering neuronal function.
The researchers eventually worked out the mechanism responsible for the neuronal destruction.
Neurons release a long form of BDNF called proBDNF, and then certain enzymes divide it to produce mature BDNF, which then nurtures brain neurons. But when proBDNF doesn’t get divided, it binds to a certain receptor and becomes toxic, killing neurons.
The same imbalance between mature BDNF and proBDNF occurs as we age, he says, and the findings suggest that a possible therapeutic intervention might involve using a small molecule to block the receptor that causes the problem.
“This finding is extremely important for both basic scientists and physicians, because it suggests a new avenue to understand, and treat, a fairly widespread cause of dementia,” he says.
Alessia Bachis, assistant professor in GUMC’s department of neuroscience, is the study’s first author. Other co-authors are Valeriya Avdoshina and Maia Parsadanian, also from the department of neuroscience, and Luigi Zecca from the Institute of Biomedical Technologies in Segrate, Italy.