A Derivative of the Brain Metabolite Lanthionine Ketimine Improves Cognition and Diminishes Pathology in the 3×Tg-AD Mouse Model of Alzheimer Disease

Abstract

Lanthionine ketimine ([LK] 3,4-dihydro-2H-1,4-thiazine-3,5-dicarboxylic acid) is the archetype for a family of naturally occurring brain sulfur amino acid metabolites, the physiologic function of which is unknown. Lanthionine ketimine and its synthetic derivatives have recently demonstrated neurotrophic, neuroprotective, and antineuroinflammatory properties in vitro through a proposed mechanism involving the microtubule-associated protein collapsin response mediator protein 2. Therefore, studies were undertaken to test the effects of a bioavailable LK ester in the 3 × Tg-AD mouse model of Alzheimer disease. Lanthionine ketimine ester treatment substantially diminished cognitive decline and brain amyloid-β (Aβ) peptide deposition and phospho-Tau accumulation in 3 × Tg-AD mice and also reduced the density of Iba1-positive microglia. Furthermore, LK ester treatment altered collapsin response mediator protein 2 phosphorylation. These findings suggest that LK may not be a metabolic waste but rather a purposeful neurochemical, the synthetic derivatives of which constitute a new class of experimental therapeutics for Alzheimer disease and related entities.

A cell-penetrating ester of the neural metabolite lanthionine ketimine stimulates autophagy through the mTORC1 pathway: Evidence for a mechanism of action with pharmacological implications for neurodegenerative pathologies

“…Treatment with LKE at pharmacologically-relevant (Hensley et al, 2013), low µM concentrations increased autophagic lipidation of LC3-I to LC3-II by 2 to 3-fold in SH-SY5Y cells with similar effects observed in RG2 glioma cells (Figs. 1–2).…”

“…At 24h in RG2 cells, LKE affected the ULK1 system with EC50 of approximately 50 nM (Fig. 3) which is 10–100 fold lower than pharmacologically achievable brain concentrations (Hensley et al, 2013) and near the reported brain physiological concentration of LK (Fontana et al, 1997). This is also within the concentration range at which LKE potentiates neurite outgrowth in NSC-34 motor neuron-like cells and primary dorsal root ganglial neurons (Hensley et al 2011; Hensley and Denton 2015).…”

“…Third, when nematodes engineered to express a partial loss-of-function Unc-33 (CRMP2) homolog mutation were allowed to develop in the presence of LKE, the compound allowed a partial rescue of these animals’ neuroanatomic phenotype (Hubbard et al, 2013). Fourth, LKE treatment normalized changes in hippocampal CRMP2 protein that occur during aging in the 3xTg-AD mouse (Hensley et al, 2013). CRMP2 is a microtubule-associated protein (MAP) that was first described as a mediator for axon retraction signals in developing neurons (Kawano et al, 2005).…”

“…Our data predict that any such CRMP2 depletion would affect autophagy with likely adverse consequences, such as are observed in AD (Pickford et al, 2008; Nixon and Yang, 2011). Conversely, agents that functionally enhance CRMP2 might mitigate some autophagy defects and may explain why LKE produced benefits on amyloid and tau burden and cognition in 3xTg-AD mice (Hensley et al, 2013) similar to effects of rapamycin in other AD models (Spilman et al, 2010; Tan et al, 2014). …”

“…A membrane-penetrating LK ester derivative (LKE) has shown potent neuroprotective and neurotrophic activities (Hensley et al, 2010a,b, 2011; Hubbard et al, 2013; Nada et al, 2012) and growth-suppressive effects towards glioma cells cortically-implanted in Fisher 344 rats (Floyd et al, 2013). Chronic oral LKE treatment diminishes amyloid burden and tau hyperphosphorylation while enhancing cognition in the 3xTg-AD mouse model of AD (Hensley et al, 2013). The precise mechanism-of-action for LKE has been unclear but is likely mediated in part through LK or LKE binding to the microtubule-associated protein, CRMP2 (collapsin response mediator protein-2) (Hensley et al, 2010a,b, 2011; Nada et al, 2012; Floyd et al, 2013; Hubbard et al, 2013).…”