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A peptide developed by Japanese researchers reversed cognitive decline in mouse models of Alzheimer’s, restoring synaptic functions. Administered nasally, the treatment targets dynamin, a protein essential to the ability of synaptic vesicles to transport neurotransmitters. Following treatment, their cognitive results were comparable to those of healthy mice.
Alzheimer’s is a progressive neurodegenerative disease manifested by cognitive decline, memory loss and ultimately the inability to perform the simplest daily tasks. Affecting nearly 55 million people worldwide, its prevalence could double by 2060 due to the aging of the population.
However, despite being the most common form of dementia, its pathophysiological mechanisms remain largely misunderstood, significantly hampering the search for treatments. Therapies available to date do not cure the disease, but only (slightly) slow its progression. On the other hand, due to its progressive nature, it is often too late to intervene once cognitive symptoms begin to appear. Therapeutic research therefore mainly focuses on early intervention strategies.
Restore synaptic vesicle functions
Among the main features of Alzheimer’s are neurofibrillary tangle induced by increased phosphorylated tau protein. At the same time, the levels of the protein in its soluble form also increase. Normally, tau proteins stabilize the structure of microtubules (the fibers constituting the cytoskeleton) in axons. However, they begin to dissociate from these as the disease progresses. Soluble monomers of the protein thus accumulate at synaptic compartments, which, in turn, accelerates neurofibrillary tangling and in
fine la destruction des synapses.
Studies have shown that synaptic dysfunction induced by increased soluble tau occurs several months before neurofibrillary tangling. This is mainly due to the impairment of the endocytic function of synaptic vesicles by the accumulation of the protein. In other words, soluble tau proteins hinder the ability of these vesicles to properly transport neurotransmitters between synapses.
Specifically, synaptic vesicles envelop (endocytosis) and transport neurotransmitters from within the synapse to the synaptic cleft, at which the neurochemical cargo is released (exocytosis). These vesicles must be constantly recycled to ensure a permanent supply of neurotransmitters. Endocytosis is regulated by a protein called dynamin, which detaches vesicles from the synaptic membrane during recycling. This protein is available in both a free form and a microtubule-bound form.
Graph showing the process of synaptic vesicle recycling. © OIST
However, in the early stage of Alzheimer’s, the increase in soluble tau protein causes an overabundance of microtubules. The latter excessively monopolize intrasynaptic dynamin, which reduces its availability for vesicular endocytosis. Researchers at the Okinawa Institute of Science and Technology (OIST) then hypothesized that inhibiting the interaction between dynamin and microtubules could prevent Alzheimer’s-related cognitive decline, before synapses are significantly damaged. irreversible manner. Their results are described in the specialized journal Brain Research.
Cognitive results comparable to those of healthy mice
To explore their hypothesis, the researchers selected transgenic mice suffering from Alzheimer’s (induced disease). To inhibit the interaction of dynamin with microtubules, they developed a small peptide called PHDP5. “ By preventing the interaction between dynamin and microtubules, PHDP5 ensures that it is available for vesicle endocytosis during recycling, which may restore lost communication between neurons at an early stage of disease », Explains Zacharie Taoufiq, co-lead author of the study, in a press release from the OIST.
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On the other hand, the researchers modified the sequence of the peptide so that it could easily penetrate inside cells. This allowed the treatment to be administered via the nasal route, which opens into a region where the blood-brain barrier is thinner and close to the hippocampus (the brain region responsible for memory). With this technique, the drug is delivered in a more targeted manner and at a higher concentration to the hippocampus, compared to other treatments. This alternative also helps minimize potential side effects associated with passage through other organs.
A) Experimental setup with a Morris water maze, in which a mouse is placed in a water bath and trained to find a hidden platform using visual cues. B) Representative illustrations of mice swimming paths to the hidden platform (white dotted line). C) Effect of intranasal administration of PHDP5 over time. © Chang et al.
The drug was found to significantly reduce dynamin-microtubule interaction, which led to effective reversal of cognitive decline in mice (tested through a maze system). This reduction was such that the learning capacity and memory of the latter were comparable to those of healthy mice. Although the treatment does not cure the disease definitively, “this success highlights the potential of targeting the dynamin-microtubule interaction as a therapeutic strategy for Alzheimer’s disease,” said author Chia-Jung Chang. principal of research. It could also be transposed to other tauopathies.
The next step in research is a move to clinical trials, which would be better supported by pharmaceutical companies, according to the researchers. While the development of a standard drug can take more than a decade, “we very much hope that our peptide can pass the tests and reach patients without too much delay,” concludes Tomoyuki Takahashi, who led the study.
