Loss of hepaCAM inhibits cholesterol biosynthesis and impairs learning and memory in mice

Cholesterol is a major astrocyte-derived substance that reprograms neuronal lipid metabolism and regulates neuronal function upon uptake by neurons. However, the mechanisms controlling cholesterol biosynthesis and secretion in astrocytes remain poorly understood. Here, we show that hepaCAM, an astrocytic membrane protein, is essential for normal memory function in mice by maintaining synaptic protein levels and synaptic spine density. Mechanistically, hepaCAM promotes neuronal function by modulating SREBP2-dependent cholesterol biosynthesis in astrocytes and facilitating its subsequent secretion. Furthermore, we identify the interaction of hepaCAM and ClC-2 is required for hepaCAM's regulatory role in cholesterol biosynthesis. Knockdown of hepaCAM in the hippocampus leads to reduced synaptic protein levels, decreased spine density, and impaired memory in mice. Collectively, our findings demonstrate that astrocytic hepaCAM regulates memory function through modulation of the astrocytic cholesterol biosynthesis pathway.