Coniferaldehyde attenuates Alzheimer's pathology via activation of Nrf2 and its targets

Abstract

Background: Alzheimer's disease (AD) currently lacks a cure. Because substantial neuronal damage usually occurs before AD is advanced enough for diagnosis, the best hope for disease-modifying AD therapies likely relies on early intervention or even prevention, and targeting multiple pathways implicated in early AD pathogenesis rather than focusing exclusively on excessive production of β-amyloid (Aβ) species.Methods: Coniferaldehyde (CFA), a food flavoring and agonist of NF-E2-related factor 2 (Nrf2), was selected by multimodal in vitro screening, followed by investigation of several downstream effects potentially involved. Furthermore, in the APP/PS1 AD mouse model, the therapeutic effects of CFA (0.2 mmol kg-1d-1) were tested beginning at 3 months of age. Behavioral phenotypes related to learning and memory capacity, brain pathology and biochemistry, including Aβ transport, were assessed at different time intervals.Results: CFA promoted neuron viability and showed potent neuroprotective effects, especially on mitochondrial structure and functions. In addition, CFA greatly enhanced the brain clearance of Aβ in both free and extracellular vesicle (EV)-contained Aβ forms. In the APP/PS1 mouse model, CFA effectively abolished brain Aβ deposits and reduced the level of toxic soluble Aβ peptides, thus eliminating AD-like pathological changes in the hippocampus and cerebral cortex and preserving learning and memory capacity of the mice.Conclusion: The experimental evidence overall indicated that Nrf2 activation may contribute to the potent anti-AD effects of CFA. With an excellent safety profile, further clinical investigation of coniferaldehyde might bring hope for AD prevention/therapy.

Coniferaldehyde ameliorates the lipid and glucose metabolism in palmitic acid‐induced HepG2 cells via the LKB1/AMPK signaling pathway

“…Dong et al. (2020) reported that the phosphorylation of GSK3β was considerably higher in cells treated with CA (10 and 100 µM). Therefore, it was speculated that CA treatment enhanced intracellular glycogen content by increasing the phosphorylation of GSK3β and decreasing the phosphorylation of GS in PA‐induced HepG2 cells.…”

“…CA is a derivative of cinnamaldehyde, which is a natural flavorant and improves liver steatosis and insulin resistance in diabetic rats (Dong et al., 2020; Zhu et al., 2017). A previous study showed that the bioavailability of cinnamaldehyde was approximately 20% after oral administration in rats (Zhao et al., 2014).…”

“…As for CA, Dong et al. (2020) reported that oral administration with high dose of CA (0.2 mmol/kg/day), not low dose of CA (0.02 mmol/kg/day), attenuated Alzheimer's pathology in mice. Furthermore, the pharmacokinetic data revealed that oral administration with CA (0.2 mmol/kg) resulted in a peak CA concentration (50 µg/g) in mice brain at about 1 hr.…”

“…Coniferaldehyde (CA), also known as 4‐hydroxy‐3‐methoxycinnamaldehyde, is a type of phenolic compound found in many edible plants, such as Cinnamomum cassia , Phyllanthus emblica , Manihot esculenta Crantz , and Codonopsis cordifolioidea (Kim et al., 2010; Mei et al., 2008; Yi et al., 2011; Zhang et al., 2016). Studies have demonstrated that CA fulfills multiple biological and pharmacological functions, which include antioxidation (Karamac, Koleva, Kancheva, & Amarowicz, 2017), anti‐inflammation (Akram et al., 2016), anti‐Alzheimer's disease (Dong et al., 2020), and antiradiation properties (Kim, Lee, Nam, Seo, & Lee, 2015). However, no existing studies are available regarding the effect of CA on the hepatic lipid and glucose metabolism.…”

Propolis and its potential against SARS-CoV-2 infection mechanisms and COVID-19 disease

“…In a mouse model of Alzheimer’s disease, coniferaldehyde, an active ingredient in propolis, had neuroprotective effects. It reduced brain β-amyloid deposits and pathological changes in the brain, helping preserve learning and memory capacity [ 156 ]. The angiotensin system, which is key to SARS-CoV-2 invasion of host cells, is associated with senescence.…”