ObjectiveTo observe the effect of scalp acupoint cluster puncture on hippocampal synaptic plasticity in APP/PS1 mice and explore the possible mechanism of scalp acupuncture cluster in improving Alzheimer's disease （AD） through the cyclic adenosine monophosphate （cAMP）/protein kinase A （PKA）/cAMP response element-binding protein （CREB） signaling pathway.MethodsMale APP/PS1 transgenic mice were randomly divided into the model group， acupuncture group， and sham acupuncture group， with 12 mice in each group. In addition， 12 C57BL/6 mice with the same genetic background were used as the control group. The acupuncture group was given scalp acupuncture cluster treatment， while the sham acupuncture group received acupuncture at non-acupoint sites under the bilateral hypochondria. Each intervention lasted 30 minutes， once a day， for a total of 28 days. The Morris water maze and Barnes maze were used to detect the learning and memory abilities of the mice. Immunohistochemistry was employed to detect amyloid-β （Aβ） deposition in hippocampal tissue. Nissl staining was used to observe the morphological changes of hippocampal tissue. Transmission electron microscopy was applied to observe the ultrastructure of hippocampal synapses in mice. Golgi staining was used to observe the dendritic spine density of hippocampal neurons. Western blot was performed to detect the protein expression of cAMP， PKA， CREB， phosphorylated （P）-CREB， postsynaptic density protein 95 （PSD95）， and synapsinⅠ （SYN1）.ResultsCompared with the control group， the model group showed prolonged escape latency and reduced platform crossings in the Morris water maze （P< 0.01）， significantly prolonged latency to enter the target hole， shortened residence time in the target quadrant of the escape box， and reduced correct hole entries in the Barnes maze （P<0.001）. The percentage of Aβ-positive expression area increased （P<0.01）， neural cells and synaptic structures in the hippocampal CA1 region were severely damaged， dendritic spine density decreased （P<0.01）， and the protein expression of cAMP， PKA， PSD-95， SYN1， and p-CREB/CREB ratio significantly decreased （P< 0.01）. Compared with the model group， the acupuncture group showed shortened escape latency and increased platform crossings in the Morris water maze （P< 0.01）， significantly reduced latency to enter the target hole， prolonged residence time in the target quadrant， and increased correct hole entries in the Barnes maze （P<0.001）. The percentage of Aβ-positive expression area decreased （P<0.01）， neural cells and synaptic structures in the hippocampal CA1 region improved， dendritic spine density increased （P<0.01）， and the protein expression of cAMP， PKA， PSD-95， SYN1， and p-CREB/CREB ratio significantly increased （P<0.01）. No significant differences were observed between the sham acupuncture group and the model group in all tests （P>0.05）.ConclusionScalp acupoint cluster puncture may enhance hippocampal synaptic plasticity in APP/PS1 mice by regulating the cAMP/PKA/CREB signaling pathway， thereby improving cognitive function in AD mice.

Scalp Acupoint Cluster Puncture;Alzheimer's disease;cAMP/PKA/CREB Pathway;Synaptic Plasticity.