Study links APOE4 gene to early neuron shrinkage and hyperactivity in mice
Researchers found that the APOE4 Alzheimer’s risk gene causes neurons to shrink and fire excessively in young mice, and that lowering the protein Nell2 can reverse these changes.
Scientists at Gladstone Institutes identified a molecular cascade whereby the APOE4 allele boosts production of Nell2, causing hippocampal neurons to become reduced in size and unusually active in young mice. This early hyperexcitability was found to forecast more severe memory deficits as the animals aged. Comparisons with APOE3 mice showed that the latter only develop similar changes much later, indicating that APOE4 accelerates an aging-like process.
Deleting APOE4 from neurons, but not from astrocytes, normalized cell size and activity, highlighting a neuron-intrinsic effect. Targeted reduction of Nell2 via CRISPRi in adult APOE4 mice enlarged neurons and dampened their firing, pointing to a reversible mechanism. The findings open the possibility of developing drugs that inhibit Nell2 to protect APOE4 carriers from Alzheimer’s-related decline.
Why it matters
It reveals a reversible early brain change linked to a major Alzheimer’s risk gene, offering a new drug target.
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