Neuroprotective Action of Coumarin Derivatives through Activation of TRKB-CREB-BDNF Pathway and Reduction of Caspase Activity in Neuronal Cells Expressing Pro-Aggregated Tau Protein

Abstract

Hyperphosphorylation and aggregation of the microtubule binding protein tau is a neuropathological hallmark of Alzheimer’s disease/tauopathies. Tau neurotoxicity provokes alterations in brain-derived neurotrophic factor (BDNF)/tropomycin receptor kinase B (TRKB)/cAMP-response-element binding protein (CREB) signaling to contribute to neurodegeneration. Compounds activating TRKB may therefore provide beneficial effects in tauopathies. LM-031, a coumarin derivative, has demonstrated the potential to improve BDNF signaling in neuronal cells expressing pro-aggregated ΔK280 tau mutant. In this study, we investigated if LM-031 analogous compounds provide neuroprotection effects through interaction with TRKB in SH-SY5Y cells expressing ΔK280 tauRD-DsRed folding reporter. All four LMDS compounds reduced tau aggregation and reactive oxygen species. Among them, LMDS-1 and -2 reduced caspase-1, caspase-6 and caspase-3 activities and promoted neurite outgrowth, and the effect was significantly reversed by knockdown of TRKB. Treatment of ERK inhibitor U0126 or PI3K inhibitor wortmannin decreased p-CREB, BDNF and BCL2 in these cells, implying that the neuroprotective effects of LMDS-1/2 are via activating TRKB downstream ERK, PI3K-AKT and CREB signaling. Furthermore, LMDS-1/2 demonstrated their ability to quench the intrinsic fluorescence of tryptophan residues within the extracellular domain of TRKB, thereby consolidating their interaction with TRKB. Our results suggest that LMDS-1/2 exert neuroprotection through activating TRKB signaling, and shed light on their potential application in therapeutics of Alzheimer’s disease/tauopathies.

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

“…As mentioned above, the hyperphosphorylation of Tau and its aggregation are typical neuropathological hallmarks of AD. Lin et al (2022) examined the protective effects of analogous compounds of LM-031 (a coumarin derivative) on SH-SY5Y cells expressing ΔK280 tauRD-DsRed folding reporter [ 62 ]. ΔK280 tauRD is a deletion mutation of Tau found in patients with tauopathies [ 63 , 64 ].…”

“…Using theΔK280 tauRD-DsRed SH-SY5Y, the authors found that the LM-031 analogs LMDS-1 to -4 reduced Tau aggregation. They also found that LMDS-1 and LMDS-2 decreased the activity of caspase-1, caspase-6, and caspase-3, and the effect was reversed after the knockdown of TrkB, suggesting involvement of the BDNF/TrkB system in neuroprotection by LM-031 analogs [ 62 ]. Using SH-SY5Y cells expressing Aβ-GFP, the protective effects of the LM-031 analogs LMDS-1 to -4 have also been demonstrated.…”

Investigating the Therapeutic Effects of Novel Compounds Targeting Inflammasome and IL-1β and IL-6 Signaling Pathways in Spinocerebellar Ataxia Type 3

“…Coumarin compound LM-021 [15] was synthesized and analyzed as described [19]. LMDS-1 and LMDS-2 [17] were obtained from Enamine (Kyiv, Ukraine). Tafamidis was supplied by Cayman Chemical (Ann Arbor, MI, USA).…”

“…LM-021 is a synthetic coumarin-chalcone derivative with anti-aggregatory, antioxidant, and neuroprotective effects in Alzheimer's Disease (AD) cell models [15]. LMDS-1 and LMDS-2, analogs of LM-031 (a synthetic coumarin-chalcone derivative), were likely to work as tropomyosin receptor kinase B (TRKB) agonists to exert neuroprotection in AD disease cell models [16,17]. Tafamidis is a compound that is commonly used to treat transthyretin amyloidosis.…”

Memantine/Aripiprazole Combination Alleviates Cognitive Dysfunction in Valproic Acid Rat Model of Autism: Hippocampal CREB/BDNF Signaling and Glutamate Homeostasis

“…The phosphorylated CREB has been shown to induce the transcription of the anti-apoptotic regulator, B-cell lymphoma 2 (Bcl-2) [ 17 ] and decrease the expression of the pro-apoptotic mediators, Bcl-2-associated X protein (BAX) and Caspase-3 [ 18 , 19 ]. Moreover, BDNF reduces the levels of the hyperphosphorylated tau protein [ 20 ] which may represent a key player in the cognitive dysfunction in autistic subjects [ 21 ].…”