The Neuroprotective Properties of the Amyloid Precursor Protein Following Traumatic Brain Injury

Abstract

Despite the significant health and economic burden that traumatic brain injury (TBI) places on society, the development of successful therapeutic agents have to date not translated into efficacious therapies in human clinical trials. Injury to the brain is ongoing after TBI, through a complex cascade of primary and secondary injury events, providing a valuable window of opportunity to help limit and prevent some of the severe consequences with a timely treatment. Of note, it has been suggested that novel treatments for TBI should be multifactorial in nature, mimicking the body’s own endogenous repair response. Whilst research has historically focused on the role of the amyloid precursor protein (APP) in the pathogenesis of Alzheimer’s disease, recent advances in trauma research have demonstrated that APP offers considerable neuroprotective properties following TBI, suggesting that APP is an ideal therapeutic candidate. Its acute upregulation following TBI has been shown to serve a beneficial role following trauma and has lead to significant advances in understanding the neuroprotective and neurotrophic functions of APP and its metabolites. Research has focused predominantly on the APP derivative sAPPα, which has consistently demonstrated neuroprotective and neurotrophic functions both in vitro and in vivo following various traumatic insults. Its neuroprotective activity has been narrowed down to a 15 amino acid sequence, and this region is linked to both heparan binding and growth-factor-like properties. It has been proposed that APP binds to heparan sulfate proteoglycans to exert its neuroprotective action. APP presents us with a novel therapeutic compound that could overcome many of the challenges that have stalled development of efficacious TBI treatments previously.