Alkaline phosphatase, tissue-nonspecific (ALPL)

Alkaline phosphatase, tissue-nonspecific (ALPL), also known as TNAP, is a membrane-bound enzyme that plays a pivotal role in skeletal mineralization by hydrolyzing inorganic pyrophosphate, a potent inhibitor of hydroxyapatite formation (UniProt P05186; Whyte, M. P., 2016). Beyond its metabolic functions in bone and liver, ALPL is highly expressed on the luminal surface of the brain microvascular endothelium, where it has been identified as a key receptor for receptor-mediated transcytosis (RMT) (Webster et al., Nature, 2024). The ALPL-mediated blood-brain barrier receptor system is currently being exploited as a delivery platform for central nervous system (CNS) therapeutics, allowing large molecules like antibodies and enzymes to cross the blood-brain barrier (BBB) with high efficiency (Denali Therapeutics, 2024). This system offers a potential advantage over traditional targets like the transferrin receptor due to its high expression levels and robust transport kinetics at the BBB. Therapeutic applications focus on treating neurodegenerative diseases and lysosomal storage disorders by engineering 'Transport Vehicles' that bind ALPL to facilitate brain entry without compromising the enzyme's physiological activity (Webster et al., Nature, 2024).

Other names

Tissue-nonspecific alkaline phosphataseTNAPTNSALPLiver/bone/kidney-type alkaline phosphataseAP-TNAPAlkaline phosphatase 2

Facilitation of receptor-mediated transcytosis (RMT) for the delivery of therapeutic agents across the blood-brain barrier via binding to the extracellular domain of the ALPL protein (Webster et al., Nature, 2024).