Novel TRKB agonists activate TRKB and downstream ERK and AKT signaling to protect Aβ-GFP SH-SY5Y cells against Aβ toxicity

Abstract

Decreased BDNF and impaired TRKB signaling contribute to neurodegeneration in Alzheimer's disease (AD). We have shown previously that coumarin derivative LM-031 enhanced CREB/BDNF/BCL2 pathway. In this study we explored if LM-031 analogs LMDS-1 to -4 may act as TRKB agonists to protect SH-SY5Y cells against Aβ toxicity. By docking computation for binding with TRKB using 7,8-DHF as a control, all four LMDS compounds displayed potential of binding to domain d5 of TRKB. In addition, all four LMDS compounds exhibited anti-aggregation and neuroprotective efficacy on SH-SY5Y cells with induced Aβ-GFP expression. Knock-down of TRKB significantly attenuated TRKB downstream signaling and the neurite outgrowth-promoting effects of these LMDS compounds. Among them, LMDS-1 and -2 were further examined for TRKB signaling. Treatment of ERK inhibitor U0126 or PI3K inhibitor wortmannin decreased p-CREB, BDNF and BCL2 in Aβ-GFP cells, implicating the neuroprotective effects are via activating TRKB downstream ERK, PI3K-AKT and CREB signaling. LMDS-1 and -2 are blood-brain barrier permeable as shown by parallel artificial membrane permeability assay. Our results demonstrate how LMDS-1 and -2 are likely to work as TRKB agonists to exert neuroprotection in Aβ cells, which may shed light on the potential application in therapeutics of AD.

Influence of microbially fermented 2´-fucosyllactose on neuronal-like cell activity in an in vitro co-culture system

“…Here ( Figures 6A – H ), we detected a slight but significant expression of TrkA ( Figure 6F ) and TrkB ( Figure 6G ) on unstimulated and ATRA-stimulated cells. Although BDNF has been found to increase the expression of TrkB as well as AChE (acetylcholine esterase) and ChAT activity (choline acyltransferase) ( 59 , 60 ), we could not see any effect produced by the stat-phase supernatants of 2´-FL metabolized by B. longum ssp . infantis ( Figure 6H ).…”

Neurotrophins and Other Growth Factors in the Pathogenesis of Alzheimer’s Disease

“…Using SH-SY5Y cells expressing Aβ-GFP, the protective effects of the LM-031 analogs LMDS-1 to -4 have also been demonstrated. Chiu et al (2022) discovered, via computational docking, that these LMDS compounds had the potential to bind to TrkB, and displayed anti-aggregation effect in SH-SY5Y cells expressing Aβ-GFP [ 65 ]. Although the overexpression of Aβ-GFP caused significant downregulation of pERK, pAkt, and pCREB, LMDS compounds restored the decreased levels of these phosphorylated molecules.…”

“…Although the overexpression of Aβ-GFP caused significant downregulation of pERK, pAkt, and pCREB, LMDS compounds restored the decreased levels of these phosphorylated molecules. The recovery effects of LMDS compounds were inhibited after the knockdown of TrkB [ 65 ].…”

Role of TrkB.T1 in Glial Inflammatory Response Elicited by MHV

“…The reverse can also been seen in a study where decreased BDNF and TrkB expressison contribute to the cognitive deficits and neurotoxicity (Chiu, et al, 2022). On the other hand, TrkB.FL agonists such as LMDS-1 and -2 can offer neuroprotective effects in rodent models of neurodegenerative diseases (Chiu, et al, 2022).…”

“…There has also been evidence that overexpression of TrkB.FL has neuroprotective effects that were associated with reduced memory impairment and depressivelike behavior (Karpova, et al, 2014;Koponen, et al, 2004) and that decreased expression of TrkB.FL is linked to neurodegerative processes (Vidaurre, et al, 2012). The reverse can also been seen in a study where decreased BDNF and TrkB expressison contribute to the cognitive deficits and neurotoxicity (Chiu, et al, 2022). On the other hand, TrkB.FL agonists such as LMDS-1 and -2 can offer neuroprotective effects in rodent models of neurodegenerative diseases (Chiu, et al, 2022).…”