Abstract
Drugs for the treatment of Alzheimer’s disease (AD) are in urgent demand due to the unmet need and the social burden associated with the disease. Curcumin has been historically considered as a beneficial product for anti-aging and AD. However, many efforts to develop curcumin for clinical use are hindered mainly due to its poor bioavailability. Recent development in drug delivery and structural design has resolved these issues. In this study, we identified a small molecule, TML-6, as a potential drug candidate for AD through screening a panel of curcumin derivatives using six biomarker platforms related to aging biology and AD pathogenesis. The structural modification of TML-6 is designed to improve the stability and metabolism of curcumin. Cell biological studies demonstrated that TML-6 could inhibit the synthesis of the β-amyloid precursor protein and β-amyloid (Aβ), upregulate Apo E, suppress NF-κB and mTOR, and increase the activity of the anti-oxidative Nrf2 gene. In the 3x-Tg AD animal model, TML-6 treatment resulted in significant improvement in learning, suppression of the microglial activation marker Iba-1, and reduction in Aβ in the brain. Although TML-6 exhibited a greater improvement in bioavailability as compared to curcumin, formulation optimization and toxicological studies are under development to assure its druggability. Taken together, TML-6 meets the current strategy to develop therapeutics for AD, targeting the combination of the Aβ cascade and aging-related biology processes.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia
We identified TML-6 as a potential AD drug candidate based on the evidence including: (I) cell biology characterization through screening a library of curcumin analogs using biomarker technology, which includes the key factors related to aging biology and AD pathogenesis as mentioned above; (II) using a triplex transgenic AD mouse model to verify the in vitro biologic effects of TML-6; (III) pharmacokinetic studies of TML-6 to evaluate the feasibility of TML-6 for future drug development
We reported for the first time that the novel curcumin analog TML-6 may represent a drugIcnanthdiisdsattuedfyor, wAeDrtehpeorratpeyd, fmoreethtiengfirtshtetcimurerethnat tsttrhaetengoyvteol cduervceulompinAaDndalrouggsTMtarLg-e6timngayatrempureltsipenlet a drug candidate for AD therapy, meeting the current strategy to develop AD drugs targeting at multiple pathways in AD pathogenesis
Summary
Alzheimer’s disease (AD) is the most common cause of dementia. It has been estimated that the total number of AD individuals will increase to approximately 74.7 million by 2030 and the cost of healthcare will increase to USD 1 trillion annually by 2050 [1]. More than hundreds of clinical trials have been conducted in the AD field in the past decades [2], only a few symptom-relief agents reach the markets. This is mainly due to the inadequate understanding of the complex pathogenesis of AD, the inappropriate design of clinical trials, and the lack of reliable diagnostic tests or biomarkers for patient inclusion [3]. In May 2018, the US National Institutes of Health organized an expert summit to discuss the strategy to develop preventive and therapeutic measures for AD control, and recommended that novel mechanistic insight and precision medicine must be enabled to clearly understand the multifaceted pathogenesis of AD, and to develop drugs targeting at combining the Aβ cascade and other disease-modifying pathways of AD [12]
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