A Curcumin Analog Exhibits Multiple Biologic Effects on the Pathogenesis of Alzheimer’s Disease and Improves Behavior, Inflammation, and β-Amyloid Accumulation in a Mouse Model

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.

Action Mechanisms of Curcumin in Alzheimer’s Disease and Its Brain Targeted Delivery

“…In India, the lower prevalence of AD compared to other countries (4.4 times lower than United States) has been attributed to a higher consumption of curcumin [ 50 , 51 ]. The literature suggests that it works via multiple mechanisms against AD [ 52 , 53 , 54 ]. The literature suggests that it inhibits β-amyloid, phospho-tau, and acetylcholineeasterase creation; modulates microglia; and chelates metal [ 4 , 55 ].…”

“…Curcumin inhibits multiple dysregulated cell-signaling pathways [ 48 ], most of which engage in crosstalk [ 53 , 54 ]. Tau phosphorylation is normally regulated by insulin and insulin-like growth factor (IGF-1), and any impairment may lead to hyperphosphorylation of tau.…”

“…Therefore, it was suggested that the mTOR pathway may be responsible for AD. Su et al [ 53 ] showed that 5.24 µg/mL of the curcumin analogue (TML-6) inhibited the phospho-mTOR pathway and decreased Aβ production. Similarly, Wang et al [ 130 ] reduced Aβ levels by downregulating the PI3K/Akt/mTOR signaling pathway.…”

Curcugreen Treatment Prevented Splenomegaly and Other Peripheral Organ Abnormalities in 3xTg and 5xFAD Mouse Models of Alzheimer’s Disease

“…There are certain advantages to use CGR for our study: (i) it is more water soluble (Figure 1A); (ii) it is 700% more potent than natural turmeric; and (iii) it can stay for a longer period (8-10 h) in the systemic circulation in comparison to the natural curcuminoids, when administered orally. As Cur is the most active compound in turmeric [34,35], we were interested to know how much free Cur was available in different tissues of mice treated with CGR for 2 months. Therefore, we measured free Cur levels from blood, liver, kidney and brain tissues from 3xTg and 5xFAD mice using ultra performance liquid chromatography (UPLC).…”

Effects of Curcumin on Aging: Molecular Mechanisms and Experimental Evidence

“…It is then not surprising that CUR has been reported to improve neuropsychological functions. CUR has several inhibitory effects on combining aging and Alzheimer's disease pathophysiology, such as the suppression of amyloid precursor protein (APP) and Aβ synthesis and the overexpression of ApoE and Nrf2 gene, as well as the prohibition of p-mTOR and p-NF-κB [106,107]. CUR prevents D-gal-induced brain aging and cognitive impairment through increments of antioxidant enzymes and inhibition of apoptosis [108].…”