Approximately 10% of HIV-positive individuals develop profound memory loss, cognitive problems and severe depression. This HIV-associated dementia closely mimics dementia typically seen in the elderly, who are decades older than the individuals most commonly infected with HIV.  What makes the brains of these young people act old before their time? The answer may lie in a small protein called a growth factor.

The cells of the body, brain cells included, are in a constantly shifting balance. Old and damaged cells undergo a form of programmed cell death known as apoptosis. While it sounds ominous, apoptosis is necessary to maintain the balance between new cell growth and cell death. Shifting the balance toward uncontrolled cell growth can result in cancer. However, when the balance shifts the other way and too many cells are destroyed, diseases can also arise. In the brain, this excess destruction of cells can lead to dementia.

Researchers at Georgetown University Medical Center discovered that HIV does not directly infect nerve cells, but instead blocks the formation of a growth factor known as mature BDNF (brain derived neurotrophic factor). When the level of this protein decreases in the brain, brain cells are unable to create the long dendritic and axonal branches required to communicate with each other, and die.

The researchers also uncovered the underlying mechanism for this premature cell death. Brain cells release a precursor to the BDNF growth factor called proBDNF. This must be divided by enzymes in the brain to release the active BDNF form, which nourishes brain cells and maintains the connections between them. HIV blocks this division, resulting in high circulating levels of proBDNF.  proBDNF binds to a receptor on brain cells that contains a ‘death domain’, triggering apoptosis (cell death).

This HIV-induced imbalance between toxic proBDNF and the healthy form of mature BDNF is similar to the imbalance seen in the aging brain. In a news release from Georgetown University, lead investigator Italo Mocchetti stated ‘“We believe we have discovered a general mechanism of neuronal decline that even explains what happens in some elderly folks. The HIV-infected patients who develop this syndrome are usually quite young, but their brains act old.” Lack of mature BDNF may also play a role in other chronic neurological conditions, including Parkinson’s and Huntington’s Diseases.

The hope is that this new research may eventually lead to the development of drugs effective in multiple forms of dementia. Blocking the receptor for proBDNF could stop the deadly cascade leading to premature cell death, and slow the relentless pace of dementia in both patients with HIV and the elderly.

References

Bachis A, Avdoshina V, Zecca L, Parsadanian M, & Mocchetti I (2012). Human immunodeficiency virus type 1 alters brain-derived neurotrophic factor processing in neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience, 32 (28), 9477-84 PMID: 22787033

Hogan C, & Wilkins E (2011). Neurological complications in HIV. Clinical medicine (London, England), 11 (6), 571-5 PMID: 22268312

Nosheny RL, Mocchetti I, & Bachis A (2005). Brain-derived neurotrophic factor as a prototype neuroprotective factor against HIV-1-associated neuronal degeneration. Neurotoxicity research, 8 (1-2), 187-98 PMID: 16260395

Wendelken LA, & Valcour V (2012). Impact of HIV and aging on neuropsychological function. Journal of neurovirology, 18 (4), 256-63 PMID: 22528478

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