The expression of two glutaminergic genes is associated with the accumulation of the TAU protein in Alzheimer’s disease

A study led by Víctor Montal, researcher at the Research Institute of the Hospital de Santa Creu i Sant Pau – IIB Sant Pau and Jorge Sepulcre, of the Massachusetts General Hospital and Harvard Medical School, in Boston (United States ) has described the association between the accumulation of the TAU protein in certain areas of the brain and the overexpression of the APOE and SLC1A2 genes in the same areas. The work has been published in the journal Science Translational Medicine.

The researchers studied the pattern of TAU spread in the brain using PET imaging techniques and studied its association with genetic data using high-resolution transcriptomic techniques. “We observed that there are specific gradients along the TAU propagation network in the brain. Specifically, we have identified 577 genes whose expression is associated with the spatial spread of TAU”, explains Víctor Montal, first signatory of the article.

Of these genes, the most relevant are APOE, which has been associated in multiple studies with Alzheimer’s disease, and SLC1A2, a glutamate transporter gene. “What we observed is that in those regions where TAU began to accumulate initially there were two genes that had much more expression compared to the regions where TAU accumulated later. In other words, the pattern of TAU accumulation was similar to the pattern of expression of these genes”, says Montal.

It has been known for years that the APOE gene is closely related to the accumulation of the beta-amyloid protein “and now several studies are showing that this gene is also closely related to the TAU protein. The function of APOE is to transport lipids in neurons and it is expressed especially in astrocytes”, explains the first author of the study.

“The other gene, SLC1A2, is a glutamate transporter. That is, it takes the neurotransmitter glutamate from the synaptic cleft and brings it into the neuron. This is very interesting because several studies have reported that excitatory neurons are more vulnerable to TAU pathology. In this way, what we have confirmed is that this gene may be responsible for this greater vulnerability in this neuronal group”.

In this sense, “the hyperexcitability of neurons has already been proposed as one of the theories that promote the accumulation of beta-amyloid protein and TAU. Our results support this theory, since those neurons where there is more expression of this glutamatergic recruiting gene are the first to accumulate TAU and to die”, in Montal’s words.

In summary, the researchers’ hypothesis is that both APOE and SLC1A2 may be responsible for promoting a selective vulnerability in some brain regions and specific neuronal populations to accumulate TAU (and not others), leading to the characteristic symptomatology of the disease Alzheimer’s. This study helps to better understand the origin and development of the disease.

Therapeutic targets

The results of this work could be useful to search for new therapeutic targets for Alzheimer’s disease and strengthen some existing theories. In fact, some trials with drugs directed against APOE, for example, are already underway in several laboratories around the world.

Another important finding of this study is that it allows predicting the areas of the brain in which the TAU protein will accumulate in the brain at very early stages. This may help to better choose candidates for a given drug, for example, targeting APOE.

Reference article

Montal V, Diez I, Kim CM, Orwig W, Bueichekú E, Gutiérrez-Zúñiga R, Bejanin A, Pegueroles J, Dols-Icardo O, Vannini P, El-Fakhri G, Johnson KA, Sperling RA, Fortea J, Sepulcre J. Network Tau spreading is vulnerable to the expression gradients of APOE and glutamatergic-related genes. Sci Transl Med. 2022 Jul 27;14(655): eabn7273. doi: 1126/scitranslmed.abn7273