Effects of ADAM10 deletion on APP shedding, synapse and synaptic plasticity in adult mice

A disintegrin and metalloproteinase 10 (ADAM10) is a member of the ADAMs (a deintegrin and metalloproteinases) family, which hydrolyzes various cellular receptors and signaling molecules (such as APP) to regulate the development of body organs and tissues. As ADAM10 is a susceptibility gene for Alzheimer's disease (AD), we generated adult neural cell-specific ADAM10 conditional knockout (ADAM10 cKO) mice to study its effects on APP shedding, synaptic integrity, and cognitive function. Our results revealed that ADAM10 deletion significantly increased levels of sAPPβ, C99, total Aβ peptides, while decreasing levels of sAPPα and C83 in the hippocampus and cortex. These changes trigger neuroinflammation, as evidenced by elevated GFAP expression. Furthermore, synaptophysin expression was reduced in the hippocampus and cortex, with postsynaptic density protein-95 (PSD-95) showing decreased expression in the hippocampal CA1 region. Synaptic ultrastructure exhibited abnormalities, and long-term potentiation (LTP) induction was impaired, ultimately leading to learning and memory deficits. These findings advance our understanding of ADAM10's biological functions and provide mechanistic insights for AD prevention and therapeutic strategies.