A hallmark of Alzheimer’s disease and dementias occurring after traumatic brain injury are “clumps” of a brain protein called tau that form in the brain. “Tau clumps” likely cause neuronal death. The tau protein is nearly identical in all species, and there is almost no difference between mouse and humans. However, only humans get Alzheimer’s disease.

Human genes differ from almost all other species (exceptions are “smart apes” like chimpanzees and gorillas) by the presence of short genetic elements, called Alu-element. We have over one million Alu elements in our DNA and Alu appearance in evolution correlated well with brain development.

Before a protein is made from a gene, the information is made into an intermediate form, a precursor. Information from this precursor is cut and pasted together, which allows the expression of multiple proteins from a gene, similar to creating a short playlist from a music library, where most of the songs are not in the playlist. Alu elements impose a structure on the precursor and this structure is specific for humans.

The intermediate between a gene and the proteins is normally linear, like an audio tape with a beginning and an end. However, some rare intermediates can be circular, like a record. We discovered such circular intermediates (circular RNAs) from the tau locus that are human specific, i.e., they are not expressed in other animals. These tau circular RNAs have part of the information for the tau protein, but they do not contain a stop signal. In a way they are like a broken record, where a scratch in the record gets the needle stuck and prevents advancing. Once the cell tries to make proteins from these tau circular RNAs, it will create large tau protein molecules by going around the circle. These large proteins are similar to what is seen in brains from people with Alzheimer’s disease.

Our basic idea is that to understand Alzheimer’s disease and dementia after traumatic brain injury, we need to use a human gene that includes all the regulatory elements in animal models, as some of these regulators, like Alu elements, are human-specific.

Our studies will be the first time the Alu regulators are tested in animals and we will therefore start with zebrafish, where we can test rapidly different experimental conditions. We already saw that some inherited human forms of dementia also cause neuronal death in fish. The zebrafish will be tested in a model of traumatic brain injury. In this model, a small metal ball is dropped on the fish’s head causing mild traumatic brain injury. Fish undergoing this treatment need longer time to memorize the path to a school of other fish, which we will test in our animal models and compare with molecular changes.

In parallel to the experiments in fish, we will test the human genes in cell models and correlate our findings with human brain samples from people with dementia. One important goal is to find out whether the human-specific tau circular RNAs actually make a protein, i.e., whether the broken record actually makes a sound, especially the same sound over and over again. We will test this idea in fish, cultured cells, and human brains. Since we know the instruction for this protein and know what it would look like, we can search for it.

If this protein exists, it will be straightforward to block its generation, which could develop in the future. Finally, zebrafish are ideal animals for initial drug screens, which could be a future application for this new animal model.