TML-6 Inhibits the Synthesis of the β-amyloid Precursor Protein and β-amyloid

Amyloid beta (Aβ) is a major component of amyloid plaques found in the brains of patients with Alzheimer’s disease. Specifically, the peptide is derived from the amyloid precursor protein (APP), which is cleaved byβ-secretase and γ-secretase to produce. Besides, Neuroinflammation and autophagy dysfunction are the most obvious pathogenesis of AD. Neuroinflammation associated with Aβ accumulation and microglial activation plays a key role in AD progression. Moreover, Aβ oligomer can induce some symptoms of Alzheimer’s disease by competing with insulin for the binding site of the insulin receptors. Thus it impairs glucose metabolism in the brain. Dysfunction of autophagy mechanism and activation of anti-aging mTOR can up-regulate APP protein hydrolysis of β- and γ-secretase. Furthermore, this leads to the production and deposition of Aβ. Therefore, inhibition of mTOR phosphorylation may provide a therapeutic strategy for AD. TML-6 inhibits the synthesis of the β-amyloid precursor protein and β-amyloid (Aβ).

TML-6 inhibits the synthesis of the β-amyloid precursor protein and β-amyloid (Aβ).

How does TML-6 work on the target? Let’s study it together. First of all, TML-6 is an orally active curcumin derivative. Meanwhile, TML-6 can upregulate Apo E, suppress NF-κB and mTOR, and increase the activity of the anti-oxidative Nrf2 gene. Nonetheless, TML-6 has the potential for Alzheimer’s disease (AD) research.

In the second place, TML-6 with 0.65-5.24 µg/mL for 24 h reduces the protein expression levels of APP and phospho-NF-κB. And TML-6 induces the protein expression level of ApoE. Importantly, TML-6 inhibits the mTOR signaling pathway through the suppression of phospho-mTOR. Particularly, TML-6 reveals no cytotoxicity in Huh-7 cells at concentrations below 5 μM and has an IC50 of 4.19 µg/mL. Interestingly, TML-6 reduces the production of Aβ40 and Aβ42 between 1.05, 2.09, and 3.14 μg/mL in a dose-dependent manner in N2a/APPswe cell. Additionally, TML-6 can exhibit transcriptional activation of the Nrf2 gene in a dose-dependent manner.

Last but not the least, TML-6 with 150 mg/kg/day by diet for four months treatment results in significant improvement in learning. Obviously, TML-6 suppresses the microglial activation marker Iba-1 and reduces Aβ in the brain. In particular, TML-6 with 150 mg/kg by oral has a T1/2 of 1.27 hours, a Cmax of 35.9 ng/mL, and an AUC of 177 ng•hr/mL.

All in all, TML-6 inhibits the synthesis of the β-amyloid precursor protein and β-amyloid.

References:

Ih-Jen Su, et al. Int J Mol Sci. 2020 Jul 30;21(15):5459.