Potential Cause of HIV-associated Dementia Revealed
July 10, 2012 - WASHINGTON - Researchers at Georgetown University Medical Center appear
to have solved the mystery of why some patients infected with HIV, who are using antiretroviral therapy and show no signs of
AIDS, develop serious depression as well as profound problems with memory, learning, and motor function. The finding might
also provide a way to test people with HIV to determine their risk for developing dementia.
They say the answer, published in the July 11 issue of the Journal of Neuroscience, may ultimately lead to a
therapeutic solution that helps these patients as well as others suffering from brain ailments that appear to develop
through the same pathway, including those that occur in the aged.
"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, Ph.D ., professor
and vice chair of the department of neuroscience at Georgetown University Medical Center. "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
a protein growth factor - mature brain derived neurotrophic factor (mature BDNF) - that Mocchetti says acts like "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, and when they lose this communication, the neurons die.
"The loss of neurons and their connections is profound in these patients," Mocchetti says. HIV-associated
dementia occurs in two to three percent of HIV-infected patients using retroviral therapies, all of who appear to be
otherwise healthy, and in 30 percent of HIV-positive patients who are not on medication.
Mocchetti believes that HIV stops production of mature BDNF because that protein interferes with the ability of
the virus to attack other brain cells. It does this through the potent gp120 envelope protein that sticks out from the viral
shell - the same protein that hooks on to brain macrophages and microglial cells to infect them. "In earlier experiments,
when we dumped gp120 into neuronal tissue culture, there was a 30-40 percent loss of neurons overnight. That makes
gp120 a remarkable neurotoxin."
This study is the product of years of work that has resulted in a string of publications. It began when Mocchetti
and his colleagues were given 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 have been or currently
are intravenous drugs users.)
They found that it was the virus that was responsible for the dementia, not the drugs, and so they set out to
discover how the virus was altering neuronal function.
Their break came when the researchers were able to study the blood of 130 women who were enrolled in the 17
year-old, nationwide Women's Interagency HIV Study, (directed at Georgetown by Mary Young, M.D.), which has focused on the
effects of HIV in infected females. In one seminal discovery, Mocchetti and colleagues found that when there was less
BDNF in the blood, patients were at risk of developing brain abnormalities. He published this finding in 2011 in the
May 15 issue of AIDS.
In this study, Mocchetti, Alessia Bachis,
Ph.D ., and their colleagues studied the brains of HIV-positive patients who had died, and who had developed HIV-associated
dementia. They also found that neurons had shrunk, and that mature BDNF had substantially decreased.
He and his colleagues then worked out the mechanism responsible for this destruction of neurons.
Normally, neurons release a long form of BDNF known as proBDNF, and then certain enzymes, including one called furin, cleave
proBDNF to produce mature BDNF, which then nurtures brain neurons. When uncut, proBDNF is toxic, leading to
"synaptic simplification", or the shortening of axons. It does this by binding to a receptor, p75NTR,
that contains a death domain.
"HIV interferes with that normal process of cleaving proBDNF, resulting in neurons primarily secreting a toxic
form of BDNF," Mocchetti says. The same imbalance between mature BDNF and proBDNF occurs as we age, he says, although no one
knows how that happens. "The link between depression and lack of mature BDNF is also known, as is the link to issues of
learning and memory. That's why I say HIV-associated dementia resembles the aging brain."
Loss of mature BDNF has also been suggested to be a risk factor in chronic diseases such as Parkinson's
and Huntington's diseases, Mocchetti says.
The findings suggest a possible therapeutic intervention, he adds. "One way would be to use a small
molecule to block the p75NTR receptor that proBDNF uses to kill neurons. A small molecule like that could get
through the blood-brain barrier.
"If this works in HIV-dementia, it may also work in other brain issues caused by proBDNF, such as aging," Mocchetti
adds.
The finding also suggests that measuring proBDNF in HIV-positive patients may provide a biomarker of risk for
development of dementia, he adds.
"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," Mocchetti 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.
Mocchetti and his co-authors report having no personal financial interests related to the study. This
work was supported by grants from the U.S. Department of Health and Human Services (1R01DA026174 and U01MH083501)
and the Latham Trust Fund.
###
Source: Georgetown University Medical Center
Contact:
Karen Mallet
(media only)
km463@georgetown.edu
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