1. The State Key Laboratories of Natural and Biomimetic Drugs and Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. Department of Pathology, University of Washington School of Medicine, Seattle, WA 98104, United States
3. Department of Anesthesiology and Perioperative Medicine, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, United States
4. Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
5. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
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.
Keywords: Alzheimer's disease, Aβ clearance, coniferaldehyde, neuroprotection, Nrf2