Overview
- The peer-reviewed Nature Aging paper published Friday reports that APOE4 made in neurons raises the protein Nell2, shrinking hippocampal neurons and making them fire too easily.
- Recordings in young APOE4 mice showed hyperactivity in two hippocampal regions that match areas reported overactive in human APOE4 carriers.
- The level of early hyperactivity predicted worse performance on later spatial learning and memory tests in the same mice.
- Cutting Nell2 in adult APOE4 mice with CRISPR interference, a method that turns down gene activity without editing DNA, restored neuron size and reduced excitability.
- Deleting APOE4 from neurons, but not from astrocytes, normalized cell size and activity, pointing to neuronal APOE4 as the driver of the circuit changes.