APOE4 gene variant shrinks brain cells years before Alzheimer's symptoms
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Gladstone Institutes researchers found that the APOE4 gene variant increases production of the protein Nell2, causing neurons to shrink and become hyperactive in young mice. Reducing Nell2 restored neuron size and firing behavior in adult APOE4 mice. The findings, published in Nature Aging, suggest a possible drug target for people with elevated Alzheimer's risk.
Key Facts
- APOE4 is carried by roughly one in four people and is estimated to occur in 60 to 75 percent of people with Alzheimer's.
- The study, published in Nature Aging, found that APOE4 increases production of the protein Nell2, which caused neurons to become smaller and unusually active in mouse models.
- Reducing Nell2 production in adult mice carrying APOE4 returned neurons toward their normal size and firing behavior.
- Mice with the greatest brain hyperactivity when young later developed the most severe memory problems.
- Young mice carrying APOE4 showed excessive neuronal activity in two areas of the hippocampus, regions also hyperactive in human APOE4 carriers.
Molecular Mechanism
Researchers at Gladstone Institutes mapped a molecular sequence linking APOE4 to early brain changes. The gene variant increases production of a protein called Nell2. Higher Nell2 levels caused neurons to become smaller and unusually active in mouse models. The study was published in Nature Aging.
Reversal Potential
The team reduced Nell2 production in adult mice carrying APOE4. Neurons returned toward their normal size and firing behavior after the reduction. The result raises the possibility that future drugs targeting Nell2 could help people with APOE4 who face an elevated risk of Alzheimer's disease.
Early Brain Activity
Earlier research found unusually high brain activity in human APOE4 carriers before middle age. Young mice carrying APOE4 showed excessive neuronal activity in two areas of the hippocampus, a brain region central to memory. Those same hippocampal regions have also been found to be hyperactive in people carrying APOE4. Mice with the greatest brain hyperactivity when they were young later developed the most severe memory problems.
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APOE4 gene variant shrinks brain cells years before Alzheimer's symptoms
