HIV associated dementia: role for neurosteroids

HIV associated dementia (HAD), is a neuronal complication of HIV infection and causes cognitive and motor impairment. The cognitive decline in HAD is due to widespread synaptic loss than neuronal loss. The neurotoxicity in HAD is caused by activation of NMDA receptors by HIV-proteins but the exact mechanism of the synaptic loss is yet to be determined. This article explores a novel pathomechanism for the observed synaptic loss. The HIV-proteins augment NMDA mediated increase of intracellular Ca(2+) in neurons which activates nNOs for Nitric Oxide (NO) synthesis. The NO activates MAPK and phosphorylates Microtubule-associated protein-2(MAP2) at specific sites causing conformational changes, microtubular disassembly and promote MAP2 degradation by the ubiquitin-proteosome pathway. Under physiological conditions Ca(2+) signaling increases cholesterol transport into mitochondria for steroidogenesis by the CYP11A1. The neurosteroid pregnenolone binds to MAP2 and causes inhibition of phosphorylation, increase in microtubule assembly and decrease MAP2 degradation. The NO can inhibits CYP11A1 in a concentration dependent manner and reduces steroidogeneisis. There is a upregulation of NO production in HAD from HIV infected microglia and astrocytes which cross neuronal membrane and increase intracellular NO. This can cause profound inhibition of steroidogenesis in the brain, increase MAP2 degradation and synaptic loss in presence of HIV-proteins.