Entorhinal Astrocyte Transplants Restore Spatial Exploration and Alleviate Amyloid‐Beta Pathology in Alzheimer's Mice

ABSTRACT Astrocytes in the medial entorhinal cortex (MEC) regulate spatial exploration, yet their functional impairment in Alzheimer's disease (AD) remains poorly understood. Here, we show that fragmented spatial exploration in APP/PS1 mice correlates with diminished exploration‐evoked Ca 2+ transients in MEC layer II astrocytes. To address this, we transplanted glial progenitor cells into the MEC of aged AD mice. The engrafted cells differentiated into homeostatic astrocytes and restored perivascular Aquaporin‐4 polarization. This remodeling significantly reduced amyloid‐beta burden, attenuated neuroinflammation, and preserved synaptic integrity. Crucially, these structural and molecular improvements specifically reversed spatial exploration deficits without affecting general locomotion. Together, our findings suggest that dysfunction in MECII astrocytes is associated with fragmented exploratory behavior. Furthermore, the region‐specific replacement of astrocytes may ameliorate the spatial exploration deficits observed in the AD mouse model.