A biological perspective of CSF lipids as surrogate markers for cognitive status in HIV

Abstract

The development and application of biomarkers to neurodegenerative diseases has become increasingly important in clinical practice and therapeutic trials. While substantial progress has been made at the basic science level in understanding the pathophysiology of HIV-Associated Neurocognitive Disorders (HAND), there are significant limitations in our current ability to predict the onset or trajectory of disease, and to accurately determine the effects of therapeutic interventions. Thus, the development of objective biomarkers is critical to further our understanding and treatment of HAND. In recent years, biomarker discovery efforts have largely been driven forward through the implementation of multiple "omics" approaches that include (but are not restricted to): Lipidomics, proteomics, metabolomics, genomics, transcriptomics, and advances in brain imaging approaches such as functional connectomics. In this paper we summarize our progress to date on lipidomic approaches to biomarker discovery, discuss how these data have influenced basic research on the neuropathology of HAND, and implications for the development of therapeutics that target metabolic pathways involved in lipid handling.

Figure 1. Metabolic pathways for sphingolipid metabolism

Sphingolipid products are shown in blue, and enzymes that catalyze these reactions are shown in red. SMase (Sphingomyelinase), SMS (Sphingomylen synthase), DES (Dihydroceramide desaturase) CERK (Ceramide kinase), CerS (Ceramide synthase), KDS (reductase= 3-keto-dihydrosphingosine reductase), SPT (Serine palmitoyl transferase), S1P Pase (Sphingosine 1-phosphate phosphatase), S1P lyase (Sphingosine 1-phosphate lyase), SphK (Sphingosine kinase), Cer1P Pase (Ceramide 1-phosphate phosphatase), GluCerS (Glucosylceramide synthase), GluCeramidase (Glucosyl ceramidase), GalCerS (Galactosylceramide synthase), LacCerS (Lactosylceramide synthase), GlyCerS, (Glycosylceramide synthase), Sulfo-GalCerS (Sulfo galactosylceramide synthase), Palmitoyl COA (Palmitoyl coenzyme A hydrolase).

Figure 2. Accumulation of Ceramide and Sphingomyelin Perturb Protein Trafficking and Endolysosomal Function

A) HIV, TNFα and IL-1β increase the size and stabilize the structure of membrane microdomains through increased ceramide formation. NMDA receptor clusters are trapped into stabilized membrane microdomains. B) Ceramide is the direct precursor to sphingomyelin. When sphingomyelin is overproduced, it becomes sequestered into lysosomes. This sequestration of sphingomyelin in lysosomes impairs the derivative capacity of endolysosomes and undegraded proteins accumulate. C) Inhibition of nSMase2 can prevent IL1β, TNFα and HIV from inducing ceramide formation. Reducing ceramide formation in this setting normalizes the lipid content of the plasma membrane and restores normal receptor trafficking. D) Agonists of the lysosomal TRPML1 channel induce the release of calcium. The release of calcium from lysosomes reduces the ionic gradient and hydrogen to be pumped into the lumen. This lowers the luminal pH and helps to clear debris through restoration of the lysosomal derivative capacity (lysosomal hydrolases have a low pH optima).