Novel social stimulation ameliorates memory deficit in Alzheimer's disease model through activating α-secretase.

As the most common form of dementia in the world, Alzheimer's disease (AD) is a progressive neurological disorder marked by cognitive and behavioral impairment. According to previous researches, abundant social connections shield against dementia. However, it is still unclear how exactly social interactions benefit cognitive abilities in people with AD and how this process is used to increase their general cognitive performance. In this study, we found that single novel social (SNS) stimulation promoted c-Fos expression, and increased the protein levels of mature ADAM10/17 and sAPPα in the ventral hippocampus (vHPC) of wild-type (WT) mice, which are hippocampal dorsal CA2 (dCA2) neuron activity and vHPC NMDAR dependent. Additionally, we discovered that SNS caused similar changes in an AD model, FAD4T mice, and these alterations could be reversed by α-secretase inhibitor. Furthermore, we also found that multiple novel social (MNS) stimulation improved synaptic plasticity and memory impairments in both male and female FAD4T mice, accompanied by α-secretase activation and Aβ reduction. These findings provide insight into the process underpinning how social interaction helps AD patients who are experiencing cognitive decline, and we also imply that novel social interaction and activation of the α-secretase may be preventative and therapeutic in the early stages of AD. Significance Statement Alzheimer's disease is a neurodegenerative disease that endangers the health of humans all over the world, yet no effective treatment is available. Here, we propose that novel social communication is able to effectively alleviate synaptic plasticity and cognitive deficits in early AD model mice. The mechanism is related to the activation of vHPC α-secretase, which alters amyloid precursor protein (APP) cleavage pathways, leading to a decrease in Aβ generation. Our findings shed light on the underlying mechanisms by which social communication improves cognition in AD models or patients and emphasize the preventive and therapeutic potential of novel social communication and α-secretase activation in the early stages of AD.