Objective:

2

To identify whether Banxia Xiexin Decoction (BXD) alleviates cerebral glucose metabolism disorder by intestinal microbiota regulation in APP/PS1 mice.

Methods:

2

Forty-five 3-month-old male APP/PS1 mice were divided into 3 groups using a random number table (

n

=15 per group)

including a model group (MG)

a liraglutide group (LG) and a BXD group (BG). Fifteen 3-month-old male C57BL/6J wild-type mice were used as the control group (CG). Mice in the BG were administered BXD granules by gavage at a dose of 6 g/(kg•d) for 3 months

while mice in the LG were injected intraperitoneally once daily with Liraglutide Injection (25 nmol/kg) for 3 months. Firstly

liquid chromatography with tandem-mass spectrometry was used to analyze the active components of BXD granules and the medicated serum of BXD. Then

the cognitive deficits

Aβ pathological change and synaptic plasticity markers

including synaptophysin (SYP) and postsynaptic density protein 95 (PSD95)

were measured in APP/PS1 mice. Brain glucose uptake was detected by micro-positron emission tomography. Intestinal microbial constituents were detected by 16S rRNA sequencing. The levels of intestinal glucagon-like peptide 1 (GLP-1) and cerebral GLP-1 receptor (GLP-1R)

as well as the phosphoinositide-3-kinase/protein kinase B/glycogen synthase kinase-3β (PI3K/Akt/GSK3β) insulin signaling pathway were determined by immunohistochemical (IHC) staining a

nd Western blot analysis

respectively.

Results:

2

BXD ameliorated cognitive deficits and Aβ pathological features (

P

<

0.01). The expressions of SYP and PSD95 in the BG were higher than those in the MG (

P

<

0.01). Brain glucose uptake in the BG was higher than that in the MG (

P

<

0.01). The intestinal microbial composition in the BG was partially reversed. The levels of intestinal GLP-1 in the BG were higher than those in the MG (

P

<

0.01). Compared with the MG

the expression levels of hippocampal GLP-1R

Akt

PI3K and p-PI3K in the BG were significantly increased (

P

<

0.01)

while the levels of GSK3β were reduced (

P

<

0.01).

Conclusion:

2

BXD exhibited protective effects against Alzheimer's disease by regulating the gut microbiota/GLP-1/GLP-1R

enhancing PI3K/Akt/GSK3β insulin signaling pathway

and improving brain glucose metabolism.