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Abstracts


Synaptic Dysfunction and Degeneration in AIDS

Mahendra Kumar, Ph.D.,
University of Miami School of Medicine


Synaptic terminals are subjected to high levels of oxidative and metabolic stress and calcium influx and are therefore sites where neurodegenerative cascades likely begin in many different disorders, including HIV dementia. We find that apoptotic biochemical cascades (caspase activation, loss of membrane phospholipid asymmetry, mitochondrial membrane depolarization, and release of factors that induce nuclear apoptosis) are activated locally in synaptic compartments in experimental models of neurodegenerative disorders such as Alzheimer's disease and stroke (Exp Neurol 153:35-48; Brain Res 807:167-76). The HIV protein Tat can also induce mitochondrial dysfunction and degeneration of synaptic terminals. Tat endangers neurons, rendering them vulnerable to excitotoxicity and apoptosis by a mechanism involving excessive calcium influx (Exp Neurol 154:276-88). We have identified a novel neuronal death-related protein called Par-4, which acts at an early step in the cell death process before mitochondrial dysfunction and caspase activation (Nature Med 4:957-62). Par-4 levels are increased in degenerating neurons in experimental models of Alzheimer's and Parkinson's diseases. Par-4 is induced at the translational level in synaptic terminals, wherein it contributes to local degenerative cascades following apoptotic triggers such as glutamate and trophic factor withdrawal. Par-4 levels are increased in hippocampal neurons in patients with HIV encephalitis, and Par-4 appears to be a key mediator of Tat-induced neuronal apoptosis (Am J Pathol 155:39-46). Collectively, the data suggest that HIV-derived proteins may promote synaptic dysfunction and degeneration, which may result in deficits in cognitive and motor functions in AIDS patients.

References

  1. Mattson, M. P., J. N. Keller and J. G. Begley (1998) Evidence for synaptic apoptosis. Exp. Neurol. 153: 35-48.

  2. Mattson, M. P., J. Partin and J. G. Begley (1998) Amyloid b-peptide induces apoptosis-related events in synapses and dendrites. Brain Res. 807: 167-176.

  3. Kruman, I., A. Nath and M. P. Mattson (1999) HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload and oxidative stress. Exp. Neurol. 154: 276-288.

  4. Guo, Q., W. Fu, J. Xie, H. Luo, S. F. Sells, J. W. Geddes, V. Bondada, V. Rangnekar, and M. P. Mattson (1998) Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer's disease. Nature Med. 4: 957-962.

  5. Kruman, I., A. Nath, W. F. Maragos, S. L. Chan, M. Jones, V. M. Rangnekar, R. J. Jakel and M. P. Mattson (1999) Evidence that Par-4 participates in the pathogenesis of HIV encephalitis. Am. J. Pathol. 155:39-46.



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