Herbal Formula Fo Shou San Attenuates Alzheimer's Disease-Related Pathologies via the Gut-Liver-Brain Axis in APP/PS1 Mouse Model of Alzheimer's Disease

Fo Shou San (FSS) is an ancient paired-herb decoction, used in China to treat blood deficiency, blood stasis, stroke, and ischemic cerebral vascular disease for about one thousand years. The mechanisms associated with these properties, however, are not completely understood. Gut bacteria, gut bacterial lipopolysaccharides (LPS), alkaline phosphatase (AP), and lipid peroxidation are common biochemical signaling that takes place on gut-liver-brain axis. Growing evidences have revealed that gut bacterial lipopolysaccharides (LPS) enter the systemic circulation via the portal vein, and finally entering the brain tissue is an important cause of inflammatory degeneration of Alzheimer's disease (AD). Alkaline phosphatase (AP) dephosphorylates LPS forming a nontoxic LPS and reduces systemic inflammation via gut-liver-brain axis. In this study, to identify the differentially gut-liver-brain axis among APP/PS1 mice, FSS-treated APP/PS1 mice, and control mice, behavioral tests were performed to assess the cognitive ability and hematoxylin-eosin staining was used to assess neuronal damage in the hippocampus; immunohistochemistry, western blotting, a quantitative chromogenic end-point Tachypleus amebocyte lysate (TAL) assay kit, Malondialdehyde (MDA) assay kit, AP Assay Kit, and real-time quantitative PCR (qPCR) were used to assess the level of LPS, MDA, AP, and gut bacteria. We found that FSS regulates gut-liver-brain axis to regulate AP and gut bacteria and attenuate the LPS-related systemic inflammation, oxidative stress (MDA), and thereby AD-related pathology in APP/PS1 mice. This is the first study to provide a reference for FSS-treated AD mice to aid in understanding the underlying mechanisms of FSS. FSS may also improve gastrointestinal tract barrier and blood-brain barrier and thus ameliorates the symptoms of AD; this is subject to our further study.