Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System

Abstract

Recent studies have highlighted the mechanisms controlling the formation of cerebral cholesterol, which is synthesized in situ primarily by astrocytes, where it is loaded onto apolipoproteins and delivered to neurons and oligodendrocytes through interactions with specific lipoprotein receptors. The "cholesterol shuttle" is influenced by numerous proteins or carbohydrates, which mainly modulate the lipoprotein receptor activity, function and signaling. These molecules, provided with enzymatic/proteolytic activity leading to the formation of peptide fragments of different sizes and specific sequences, could be also responsible for machinery malfunctions, which are associated with neurological, neurodegenerative and neurodevelopmental disorders. In this context, we have pointed out that purines, ancestral molecules acting as signal molecules and neuromodulators at the central nervous system, can influence the homeostatic machinery of the cerebral cholesterol turnover and vice versa. Evidence gathered so far indicates that purine receptors, mainly the subtypes P2Y₂, P2X₇ and A_2A, are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's and Niemann-Pick C diseases, by controlling the brain cholesterol homeostasis; in addition, alterations in cholesterol turnover can hinder the purine receptor function. Although the precise mechanisms of these interactions are currently poorly understood, the results here collected on cholesterol-purine reciprocal control could hopefully promote further research.

Keywords: LDL receptors; cholesterol; purinergic receptors.

Figure 1

In normal conditions, ATP is released from virtually all cells by multiple ways, i.e., vesicular exocytosis, facilitated diffusion by nucleotide-specific ATP-binding cassette (ABC) transporters, connexin/pannexin (Cx/Panx) hemichannels and multiple organic anion transporters. In contrast, adenosine is mainly generated from the extracellular nucleotide metabolism while adenosine efflux from cells usually occurs under cell stress conditions by selective carriers (ENT/CNT) [101]. Purines are also extracellularly metabolized. The principal family of ATP-metabolizing enzymes are the nucleoside triphosphate diphosphohydrolases (NTPDases), which consist of eight members, of which NTPDase 1, 2, 3, and 8 are cell surface-bound enzymes, with different activities. Extracellular ATP can also be metabolized by enzymes belonging to the family of ectonucleotide pyrophosphatases (ENPPs) and acid phosphatases (APs). AMP, derived from ATP metabolism, is degraded to adenosine (ADO) mainly by ecto-5′-nucleotidases (5′-NT, also known as CD73). Once formed, ADO can be further metabolized at an extracellular level up to hypoxanthine by the combined activity of cell surface-located enzymes, i.e., adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP), or transported into the cell by specific transporters to fill the intracellular pool of adenine nucleotides [102]. ENT: equilibrative nucleoside transporter; CNT: concentrative nucleoside transporter.