title: Regulation of structural and functional synapse density by L-threonate through modulation of intraneuronal magnesium concentration.
abstract: Oral administration of the combination of L-threonate (threonate) and magnesium (Mg(2+)) in the form of L-Threonic acid Magnesium salt (L-TAMS) can enhance learning and memory in young rats and prevent memory decline in aging rats and in Alzheimer's disease model mice. Recent results from a human clinical trial demonstrate the efficacy of L-TAMS in restoring global cognitive abilities of older adults. Previously, we reported that neuronal intracellular Mg(2+) serves as a critical signaling molecule for controlling synapse density, a key factor that determines cognitive ability. The elevation of brain Mg(2+) by oral administration of L-TAMS in intact animals plays a significant role in mediating the therapeutic effects of L-TAMS. The current study sought to elucidate the unique role of threonate. We aimed to understand if threonate acts directly to elevate intraneuronal Mg(2+), and why Mg(2+) given without threonate is ineffective for enhancing learning and memory ability. We discovered that threonate is naturally present in cerebrospinal fluid (CSF) and oral treatment with L-TAMS elevated CSF threonate. In cultured hippocampal neurons, threonate treatment directly induced an increase in intracellular Mg(2+) concentration. Functionally, elevating threonate upregulated expression of NR2B-containing NMDAR, boosted mitochondrial membrane potential (ΔΨm), and increased functional synapse density in neuronal cultures. These effects are unique to threonate, as other common Mg(2+) anions failed to have the same results. Mechanistically, threonate's effects were specifically mediated through glucose transporters (GLUTs). We also evaluated the effects of threonate in human neural stem cell-derived neurons, and found it was equally effective at upregulating synapse density. The current study provides an explanation for why threonate is an essential component of L-TAMS and supports the use of L-TAMS to promote cognitive abilities in human.
authors.affiliation: School of Medicine, Tsinghua University, Beijing, 100084, China.
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Neurocentria, Inc., Fremont, CA 94538, USA.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Weinger
authors.affiliation: Neurocentria, Inc., Fremont, CA 94538, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Mao
authors.affiliation: School of Medicine, Tsinghua University, Beijing, 100084, China; Neurocentria, Inc., Fremont, CA 94538, USA. Electronic address: gliu@neurocentria.com.
authors.forename: Guosong
authors.initials: G
authors.lastname: Liu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002087:Butyrates / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D002478:Cells, Cultured; D005333:Fetus; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism*; D008297:Male; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
chemical_list: D002087:Butyrates; D008274:Magnesium; C011369:threonic acid
keywords: Functional terminals; Human stem cell-derived neurons; Intracellular Mg(2+); Rat; Synaptic density; Threonate