The complex pathogenesis of Alzheimer's disease (AD) leads to a limited therapeutic effect; therefore, the combination of multiple bioactive ingredients may be more effective in improving AD due to synergistic effects. Based on the perspective of the sea–land combination, the effects of sea-derived Antarctic krill oil (AKO) combined with land-derived nobiletin (Nob) and L-theanine (The) on memory loss and cognitive deficiency were studied in senescence-accelerated prone 8 mice (SAMP8). The results demonstrated that AKO combined with The significantly increased the number of platform crossings in the Morris water maze test by 1.6-fold, and AKO combined with Nob significantly increased the preference index in a novel object recognition test. AKO exhibited synergistic effects with Nob and The in ameliorating recognition memory and spatial memory deficiency in SAMP8 mice, respectively. Further research of the mechanism indicated that AKO exhibited synergistic effects with Nob in suppressing β-amyloid (Aβ) aggregation, neurofibrillary tangles, and apoptosis and neuroinflammation, while the synergistic effects of AKO and The involved in synaptic plasticity and anti-neuroinflammation, which revealed that the combination was complex, not a mechanical addition. These findings revealed that the sea–land combination may be an effective strategy to treat and alleviate AD.

Blood−brain barrier (BBB) impairment is related to the development of Alzheimer's disease (AD), which is dependent not only on tight junction but also on transcytosis of brain endothelial cells (BECs) in the BBB. Aging induces the decrease of ligand-specific receptor-mediated transcytosis (RMT) and the increase of non-specific caveolar transcytosis in BECs, which lead to the entry into parenchyma of neurotoxic proteins and the smaller therapeutic index in central nervous system drug delivery, further provoking neurodegenerative disease. A previous study suggests that sea-derived Antarctic krill oil (AKO) exhibits synergistic effects with land-derived nobiletin (NOB) and theanine (THE) on ameliorating memory and cognitive deficiency in SAMP8 mice. However, it is still unclear whether BBB change is involved. Hence, the effects of AKO combined with NOB and THE on aging-induced BBB impairment, including tight junction between BECs, ligand-specific RMT, and non-specific caveolar transcytosis in BECs, are investigated. The results suggest that AKO exhibits synergistic effects with NOB and THE on regulating ligand-specific RMT in BBB by inhibiting alkaline phosphatase (ALPL). The study provides a potential strategy candidate or targeted dietary patterns to prevent and treat AD by improving the BBB function.

Nobiletin (Nob) is reported to exhibit neuroprotective properties, which is limited by its low oral bioavailability. Antarctic krill oil (AKO) is abundant in n‐3 polyunsaturated fatty acids in the form of phospholipids, which exhibit an amphiphilic property. It is unclear whether AKO can enhance the bioavailability of nobiletin to facilitate the combined effect on neuroprotection. In the present study, the absorption of Nob carried by AKO is significantly enhanced in contrast to that suspended in corn oil. Moreover, Aβ1–42 injected rats are utilized to clarify the effect of the combination of Nob and AKO on improving the memory and learning ability. Results present that the combination of AKO and Nob significantly reverses the cognitive and learning defects induced by Aβ1–42 injection, but does not have ideal synergistic effect compared to AKO or Nob alone treated groups. Further molecular experiments imply that the neuroprotective effect may be attributed to the reduction of oxidative stress, the inhibition of apoptosis and tau phosphorylation, as well as the improvement of the neurotrophic activity. This study provides scientific insights and theoretical guidance for the nutritional interventions of the combined development of nobiletin and AKO to prevent neuropsychiatric disorders.