Protective effects of CCL01 against A beta-induced neurotoxicity in 5xFAD transgenic mouse model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common dementia characterized by the excessive accumulation of amyloid-beta (A beta) and tau aggregates, as well as neuronal damage and neuroinflammation. Metabolic disruption in AD has been noticed because metabolite alterations closely correlate with A beta neuropathology and behavioral phe-notypes. Accordingly, controlling various neuropathological processes and metabolic disruption is an efficient therapeutic strategy for AD treatment. In this study, we evaluated the effects of a combination of Cuscuta seeds and Lactobacillus paracasei NK112 (CCL01) on AD neuropathology and altered metabolism in five familial AD (5xFAD) transgenic mice and neuronal cell cultures. First, we observed that CCL01 exerted neuroprotective ef-fects in HT22 hippocampal neurons and primary cultured neurons. CCL01 ameliorated memory decline and protected synapses and neuronal survival in 5xFAD mice. These effects were related to the inhibition of tau phosphorylation. CCL01 also inhibited the activation of mitogen-activated protein kinase (MAPK) signaling and neuroinflammatory processes. Moreover, the metabolite profile-particularly characterized by altered phos-pholipid metabolism-was significantly changed in the 5xFAD group, while CCL01 partly restored the alteration. Lysophosphatidylcholine (lysoPC), the levels of which were higher in the brains of 5xFAD mice, exerted neurotoxicity in vitro, whereas CCL01 protected neurons from lysoPC-induced toxicity by regulating MAPK signaling. Additionally, CCL01 administration reduced gut inflammation in the 5xFAD mice. In summary, we demonstrated that CCL01 improved the memory function of 5xFAD mice by protecting neurons against A beta-and lysoPC-induced toxicity through the regulation of MAPK signaling, neuroinflammation, tau phosphorylation, and gut inflammation, suggesting the potential of CCL01 as treatment for AD.