Alzheimer’s disease can be difficult to deal with because it changes a loved one into a person who barely recognizes us. Many people wonder why their memory and personality slip away. Scientists have discovered that a major cause of Alzheimer’s is the buildup of a brain protein called tau.
Normally, tau proteins keep our nerve cells healthy by stabilizing their “train tracks,” called microtubules, and helping move nutrients through them. But in patients with Alzheimer’s, tau proteins twist and tangle, clogging the system and disrupting communication between cells. Doctors now recognize these tau tangles as a defining feature of Alzheimer’s and a predictor of brain decline.
Though tau tangles may explain brain decline in Alzheimer’s patients, researchers have also found that inheriting the gene apolipoprotein E4 or APOE4 has a strong linkage to late-onset Alzheimer’s and can promote tau tangles. APOE4 codes for a protein that carries fats and cholesterol to nerve cells and other cells in the brain.
A team of researchers at the University of California, San Francisco, and the Gladstone Institute found that removing APOE4 from nerve cells can reduce brain issues related to Alzheimer’s. They discovered this by observing specially bred mice that carried tau tangles and different forms of the human APOE gene. Some mice carried the APOE4 gene while others carried a different form of the APOE gene, called APOE3. The researchers wanted to test whether the APOE4 inside the mice’s nerve cells directly drove Alzheimer’s-like brain damage, and whether removing APOE4 could protect their brains from declining.
To test whether the APOE4 gene acted as a contributor or a side effect, they surgically inserted viruses carrying an abnormal tau protein into one side of each mouse’s hippocampus. When the mice were 10 months old, the researchers tested the specially bred mice with the APOE3 and the APOE4 genes. They examined how much tau protein built up in the mice’s brains when the APOE4 gene was present compared to when it was absent, using MRI scans, brain regions stained with 2 different dyes, microscopes, brain activity tests, and RNA sequencing.
The researchers found differences in tau tangles, brain decline, and other issues that characterize Alzheimer’s disease in both types of mice. The mice with the APOE4 gene had more tau tangles, brain decline, and nerve cell death. The mice with the APOE3 gene barely had any tau tangles within the brain, and no signs of brain decline.
Next, the researchers used a protein connected to an enzyme called CRE to cut out the APOE genes inside the mice’s nerve cells, and measured their tau tangles with a special dye. When they clipped out the mice’s APOE4 genes, the researchers found that the tau tangles decreased from almost 50% to roughly 10%. In the mice carrying the APOE3 gene, the researchers observed that the percentage of tau tangles decreased from a little under 10% to about 3%.
They used another dye to measure a similar clump of proteins also found in Alzheimer’s patients, called amyloid plaques. Their results showed that amyloid plaques decreased from about 20% to under 10% after they removed the mice’s APOE4 gene. In contrast, the percentage of amyloid plaques in mice carrying the APOE3 gene did not significantly change, remaining at about 10%.
The researchers also sequenced the mice’s RNA to determine how the APOE4 gene affected their nerve cells and other brain cells. They found that the presence of APOE4 in the mice triggered an increase in Alzheimer’s-related brain cells. It also helped the researchers demonstrate that the removal of APOE4 from the mice’s nerve cells calmed the Alzheimer’s-related responses.
Overall, the researchers concluded that APOE4 is harmful and can actively drive Alzheimer’s-like damage in mice’s brains. While their results need to be confirmed in humans, they stated that this gene could someday help develop medications to treat Alzheimer’s disease.
