Neuroprotective Effects of Icariin on Brain Metabolism, Mitochondrial Functions, and Cognition in Triple‐Transgenic Alzheimer's Disease Mice

Summary Aims This study investigated the neuroprotective properties of icariin (an effective component of traditional Chinese herbal medicine Epimedium) on neuronal function and brain energy metabolism maintenance in a triple‐transgenic mouse model of Alzheimer's disease (3 × Tg‐AD). Methods 3 × Tg‐AD mice as well as primary neurons were subjected to icariin treatment. Morris water maze assay, magnetic resonance spectroscopy (MRS), Western blotting, ELISA, and immunohistochemistry analysis were used to evaluate the effects of icariin administration. Results Icariin significantly improved spatial learning and memory retention in 3 × Tg‐AD mice, promoted neuronal cell activity as identified by the enhancement of brain metabolite N‐acetylaspartate level and ATP production in AD mice, preserved the expressions of mitochondrial key enzymes COX IV, PDHE1α, and synaptic protein PSD95, reduced Aβ plaque deposition in the cortex and hippocampus of AD mice, and inhibited β‐site APP cleavage enzyme 1 (BACE1) expression. Icariin treatment also decreased the levels of extracellular and intracellular Aβ1‐42 in 3 × Tg‐AD primary neurons, modulated the distribution of Aβ along the neurites, and protected against mitochondrial fragmentation in 3 × Tg‐AD neurons. Conclusions Icariin shows neuroprotective effects in 3 × Tg‐AD mice and may be a promising multitarget drug in the prevention/protection against AD.