Converging roles for sphingolipids and cell stress in the progression of neuro-AIDS

Abstract

Sphingolipids are a class of lipids enriched in the central nervous system that have important roles in signal transduction. Recent advances in our understanding of how sphingolipids are involved in the control of life and death signaling have uncovered roles for these lipids in the neuropathogenesis of HIV-associated neurocognitive disorders (HAND). In this review we briefly summarize the molecular mechanisms involved in the pathological production of the toxic sphingolipid, ceramide and address questions of how cytokine and cellular stress pathways that are perturbed in HAND converge to deregulate ceramide-associated signaling.

HIV Infection and Aging Independently Affect Brain Function as Measured by Functional Magnetic Resonance Imaging

“…Although we did not directly correlate neuroimaging measures with markers of brain immune dysfunction, it is reasonable to hypothesize that persistent low levels of HIV and inflammation may deplete brain reserves augmenting functional metabolic requirements. Observed increases in metabolic demands could result from excessive neurotransmission from oxidative stress signaling pathways [15]. Multiple neurodegenerative and neuroimmune mechanisms may converge in older HIV+ individuals.…”

The Role of the Ceramide Acyl Chain Length in Neurodegeneration: Involvement of Ceramide Synthases

“…The combined findings from these studies suggest that SM and ceramides with fatty acid chain lengths of C16 and C24 are dysregulated in the brains of patients with HIV-associated neurological disorders (Haughey et al 2008). To date, no studies have examined the expression levels of the CerS proteins in HIV infection, so it is currently not possible to distinguish between the potential roles of changes in CerS expression or activity versus changes in the activity of other enzymes that metabolize SLs.…”

Neurodegeneration and Ageing in the HAART Era

“…Interestingly, this pattern of impaired retrieval and preserved long-term storage (when aided with cues) is also predominant in HAND in addition to learning deficits. In both conditions, the pattern of effortful learning/recall disturbances has been interpreted as being partially dependent on working memory deficits and slowing of cognitive processes (Peavy et al 1994;Hartley 2006). Another interpretative framework that has been proposed in ageing research is that of a deficiency of executive control (West 1996).…”

“…Furthermore, nitrosative stress with peroxynitrite formation leading to modification of tyrosines in proteins is considered to enhance the aggregation of α-synuclein which in turn is pathogenetically significant in Parkinson's, Lewy body dementia, progressive supranuclear palsy, multisystem atrophy, as well as HAND (Haughey et al 2008;Li et al 2008).…”