In Alzheimer’s disease, therapeutic research has mainly focused on anti-amyloids, with mixed success. A team targeted the pathological Tau protein by developing a peptide capable of inhibiting its aggregation. A path to explore!
Alzheimer’s disease is a neurodegenerative proteinopathy, which is characterized by the accumulation of extracellular plaques composed of β-amyloid (Aβ) peptide and intracellular neurofibrillary tangles of hyperphosphorylated Tau protein. These protein aggregates are responsible for the neurodegeneration and cognitive decline associated with the disease.
At the time of writing, only the anti-amyloid antibody donanemab has demonstrated moderate effectiveness in phase III, in patients with mild dementia, both in reducing amyloid mass and slowing cognitive decline. It thus received marketing authorization in the United States in July 2024 and in Great Britain on October 23.
Inhibit the aggregation of hyperphosphorylated Tau protein
Inhibition of the formation of intracellular aggregates of the Tau protein, whose physiological role is to stabilize microtubules and participate in the integrity of the axon cytoskeleton, is also a potential therapeutic objective. It could involve inhibition of Tau phosphorylation or reduction of Tau expression using antisense oligonucleotides. To date, with the exception of methylene blue derivatives for which a phase III has just been completed (unpublished results), these strategies have not progressed beyond the pre-clinical stage.
For an inhibitor of Tau protein aggregation to be potentially clinically relevant for all tauopathies, it must: 1) target not just one but both hexapeptides involved in neurotoxic Tau aggregation (275VQIINK280et 275VQIINK280in order to inhibit the aggregation of the six isoforms of Tau; 2) be stable against proteolysis; 3) cross the blood-brain barrier and 4) reverse alive Tau phenotypes dependent on intracellular neurofibrillary aggregation.
An innovative, effective and non-toxic retro-inverted peptide in vitro et alive
After a long development and screening work, Aggidis et al. present a retro-inverted D peptide* (RI-AG03) bringing together all these properties. Able to bind to both hexapeptides 275VQIINK280et 275VQIINK280it showed its stability and its ability, in a model of human embryonic kidney cells, to cross the cell membrane and inhibit Tau aggregation. Furthermore, in a model alive of transgenic fruit flies suffering from Tau-induced ocular neurodegeneration, RI-AG03 administered in food proved capable of reversing the anatomical disorganization of the eyes but also of extending the lifespan of the animals. Whether in vitro or alivethe peptide did not present any toxicity. Its mode of action involves reducing the formation of beta sheets within Tau monomers, that is to say secondary structures responsible for the parallel association of monomers then, at a more advanced stage, for the formation of insoluble protofilaments found in neurotoxic intracellular neurofibrillary tangles.
The authors conclude by emphasizing the unique ability to date of their retro-inverted peptide to inhibit the two sites responsible for the neurotoxic aggregation of Tau, pleading for clinical testing of this peptide in tauopathies such as Alzheimer’s disease. , after validation in a mammalian animal model.
* A retro-inverted D-peptide is a peptide composed of amino acids from the D series (and not L as in natural peptides) and whose primary sequence is inverted with respect to a reference peptide of which it is therefore the double image in a mirror.
