Collapsin response mediator protein 2 (CRMP2), traditionally regarded as an axon/dendrite growth and guidance protein, plays an important role in the regulation of both post-and pre-synaptic Ca2+ channels, such as N-methyl-d-aspartate receptors (NMDARs). The Ca2+ channel-binding domain 3 (CBD3) peptide derived from CRMP2 has recently emerged as a Ca2+ channel blocker, suppressing neuropathic pain in a spared nerve injury (SNI) model when linked to the transduction domain of HIV TAT protein and reduced neuronal death in a middle cerebral artery occlusion model and a traumatic brain injury (TBI) model. The present study aimed to examine the neuroprotective effects and biochemical mechanisms of ST2-104 (a non-arginine-conjugated CBD3 peptide) in an A beta(25-35)-induced Alzheimer's disease (AD) rat model. This study demonstrated that CRMP2 and NMDARs subunit NMDAR2B form a direct biochemical complex, which regulates NMDAR activity in a rat model. ST2-104 peptide given via tail vein injections significantly reduced spatial learning and memory impairment. ST2-104 relieved neuronal injuries by suppressing expression of NMDAR2B and p-CRMP2 and increasing expression of CRMP2 in the hippocampus. Remarkably, ST2-104 attenuated levels of intracellular Ca2+ by disrupting the interaction between p-CRMP2 and NMDAR2B. Taken together, these findings support ST2-104 as a novel neuroprotective agent, potentially representing a novel direction for a therapeutic targeting channel in AD.National Natural Science Foundation of China [81571231]; Health and Family Planning Commission of Jilin Province [2015Z043]; Department of Education Foundation of Jilin Province [JJKH20190102KJ]; Department Science and Technology Foundation of Jilin Province [20190701058GH]; Talent Development Fund of Jilin ProvinceOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
