The leading cause of neurological disability, Alzheimer's disease manifests itself as the progressive and irreversible loss of various cognitive functions, especially memory. At the level of lesions, it is particularly characterized by hyperphosphorylation[1] of the Tau protein and its accumulation in the form of aggregates in several cell types. Among the different types of intracellular Tau aggregates contained in neurons, neurofibrillary degeneration (NFD), comprising highly aggregated forms of Tau, has long been considered responsible for the neurodegeneration of patients. Indeed, their numbers are strongly correlated with neuronal death and cognitive decline. Nevertheless, neuronal death and NFD do not appear in the same areas of the brain. In addition, studies have shown in transgenic mouse models that neurons in which NFD accumulates can survive and even communicate with each other. Thus, it was hypothesized that complex soluble forms of Tau presenting an intermediate state of aggregation (i.e. oligomeric forms) may be more toxic than NFD.

Teams from the CEA's Institut François-Jacob, in collaboration with researchers from the Servier laboratory, the Université Lille 2 and the Ludwig Maximilian University of Munich, have sought to elucidate the toxicity of NFD in vivo. "We developed a model of the disease in rats, called the pro-aggregation model, which generates a large amount of NFD in the hippocampus, an area of the brain that plays a central role in memory," explains Karine Cambon, a researcher at the CEA. Human wildtype Tau protein and a peptide that induces Tau aggregation (pro-aggregation peptide) are produced through the injection of gene transfer vectors. "In this model, we observe a pathological hyperphosphorylation of the Tau protein, an aberrant localization of the protein in neurons, and the presence of many NFDs as early as one month after injection of the vector, similar to the lesions found in patients," continues the researcher. "By counting the number of neurons in the hippocampus, we have shown that the presence of NFD does not cause neuronal death until at least 3 months after injection." Surprisingly, the study shows that when wildtype human Tau protein is over-expressed by itself without the pro-aggregation peptide, Tau is more strongly hyperphosphorylated, NFDs are not present, and significant neuronal death is induced in the hippocampus!

In vivo, large aggregates of Tau would therefore seem to be harmless to neurons, at least initially, whereas the soluble forms (probably oligomeric) would be the most toxic. Moreover, the study shows that the amount of NFD imperfectly reflects the severity of the pathology, whereas the hyperphosphorylation of Tau would be a much better indicator of neurodegeneration. "Our study suggests that it is certainly more appropriate to develop imaging tracers and therapeutic agents capable of specifically targeting these soluble forms of Tau rather than NFDs," concludes Karine Cambon.

[1] Phosphorylation is a chemical modification that corresponds to the addition of a phosphate group to a molecule. The phosphorylation of proteins is commonplace and classically occurs in the regulation of protein activity.