A study led by Stanford Medicine finds that genes protect against Alzheimer’s and Parkinson’s

Mignot thinks that DR4 is involved in what is called “protective autoimmunity”: The specific peptide that DR4 knows how to capture and express is actually part of a normal protein produced by our cells – tau. It is the chemical change that causes the problem.

A tau connection?

Noticing the beneficial effects of DR4 on tau levels and pathologies in both Alzheimer’s and Parkinson’s, researchers have gone into tau. They cut protein molecules into 482 peptides together taking the overall sequence of tau, then put them in different dishes with the protein product DR4 (also called DR4) to see if it binds more to any of those peptides.

In addition, the researchers tested all the possible biological changes each of those peptides could accumulate once they are produced inside the cell.

DR4 binds strongly to one peptide. Called PHF6, this part of the tau protein is often altered in the brains of Alzheimer’s patients through a change called acetylation – the addition of a small chemical clump to one of the building blocks of the protein in that part. Acetylated PHF6 has been implicated in tau molecules’ tendency to aggregate into neurofibrillary tangles.

“The only peptide DR4 bound strongly was PHF6 – and then only when this peptide was acetylated,” says Mignot. It is already known that PHF6 acetylation facilitates tau aggregation into neurofibrillary tangles, he noted.

Acetylation can “trick” the immune system into thinking that PHF6 is foreign and dangerous, Mignot said, leading the immune system to attack and destroy the neurofibrillary tangles.

He thinks it might be possible to make DR4 less active in carriers by creating a vaccine that includes acetylated PHF6. By attracting the immune system’s attention to this modified peptide, such a vaccine could interfere with tau assembly. For people who carry any protective form of DR4 (not all are protective) and whose brains have begun to accumulate tau aggregates, the vaccine may delay the onset or slow the progression of Alzheimer’s and Parkinson’s, Mignot suggested.

People who do not carry DR4 will not benefit from the vaccine, Mignot said. Furthermore, DR4 comes in a series of subtypes, separated by slight differences in the gene sequence. Of the six or seven most common types of DR4, one may be more common in people of one ancestry, while others may be more prevalent in people of other ancestries. The DR4 subtype that is more common among East Asians does not appear to be as helpful in preventing neurodegenerative disease as the DR4 subtype is more common in other populations, for example.

A blood test should be offered to determine who should or should not be vaccinated, Mignot said.

Stanford University’s technology licensing office has applied for a patent on intellectual property related to the results of this study.

Approximately 160 additional researchers from multiple institutions in approximately 25 countries contributed to this work.

The study was funded by the National Institutes of Health (grants AG060747, AG066206 and AG066515), the European Union, the Michael J. Fox Foundation, the Alzheimer’s Association, the Iqbal Farrukh and Asad Jamal Fund, Alzheimer DNA BioBank of Europe, Japan. Agency for Medical Research and Development, Einstein Center for Neurosciences in Berlin, Swedish Research Council, European Research Council, and Swedish National Support for Clinical Research.