The modulatory effects of Hericium erinaceus and donepezil on amyloid accumulation and autophagy-associated clearance in Aβ 1-42 -induced N2a cells
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Background and objective
Alzheimer’s disease involves imbalanced amyloid-β (Aβ) production and clearance, supporting investigation of adjuncts to symptomatic treatment. This study evaluated whether methanolic Hericium erinaceus extract could support recovery after Aβ 1-42 -induced injury, alone and with donepezil, through modulation of β-secretase (BACE1) activity or autophagy-associated clearance.
Methods
Extract composition and BACE1 inhibition were assessed using liquid chromatography-mass spectrometry (LC-MS) and a fluorescence resonance energy transfer assay, respectively. Neuro-2a cells exposed to Aβ 1-42 (2.42 µM) for 6 hours received individual or combined treatments for 24 hours. Cell viability was assessed using WST-1, combination interactions using Bliss independence and protein responses using Western blotting with paired bafilomycin A1 conditions across three independent experiments.
Results
LC-MS identified ergothioneine and trace hericenone D. The extract produced an apparent concentration-dependent BACE1-inhibitory response (IC 50 , 69.97 ± 36.10 µg/mL) and significantly increased post-injury viability at 40 µg/mL (150.2 ± 12.11% of the Aβ-induced control; p = 0.0070). Although the full combination matrix was predominantly additive (Bliss score, 1.95), 51.1 µM donepezil with 24.9 µg/mL extract produced local synergy (score, 34.29) and the highest observed viability. This pair showed the most coordinated directional protein pattern, with lower mean levels of amyloid precursor protein, Aβ and BACE1, and p62/Aβ accumulation following lysosomal blockade. Western blot differences were not statistically significant.
Conclusion
These integrated findings support H. erinaceus as a candidate adjunct to donepezil, with possible complementary effects on amyloidogenic processing and intracellular clearance. Further validation of autophagic flux is needed to confirm the proposed dual response.
