For many years, the laboratory of Dr. Jean Charles Lambert is one of the world leaders in research on the Alzheimer's disease, particularly in the study of its genetic component. His work has greatly contributed to the identification of most of the genetic factors involved in the development of this disease. Among them, the gene apoe is the main known genetic risk factor, followed by the gene BIN1.
BIN1: a gene closely linked to Alzheimer's disease
The BIN1 gene plays an important role in theendocytosis. In humans, more 10 isoforms, that is to say different versions, of BIN1 exist but their function and their precise role in Alzheimer's disease remain poorly understood.
What is endocytosis? Endocytosis It is a mechanism that allows cells tointernalize moleculesThis process is essential for the proper functioning of neurons. Indeed, neurons communicate with each other thanks to... synapses, via the release of vesicles containing chemical molecules, called neurotransmittersThese molecules are then captured by the neighboring neuron to ensure the transmission of the nerve impulse. This communication requires a permanent recycling synaptic components, in which endocytosis plays a role. This is all the more relevant because BIN1 is located at the synapses.
Within Dr. Jean-Charles Lambert's team, the Dr. Erwan Lambert, under the direction of Drs Pierre Dourlen and Devrim Kilinc, and their collaborators focused on three isoforms of BIN1:
- Isoforms 1 et 9 of BIN1, expressed in the brain, isoform 1 being even specifically expressed in the neurons
- The isoform 8 of BIN1, which is not expressed in the brain.
To study their effects, the researchers used a model of fruit fly (vinegar fly) each expressing one of these human isoforms. Drosophila is a valuable research model because the functions of human BIN1 are conserved in it.
A version of BIN1 that is particularly harmful to neurons
The results of this study highlighted that only the BIN1 isoform 1 alters synaptic function. Indeed, neurons expressing this isoform exhibit a loss of their electrophysiological activity, sign of a less efficient information transmission between neurons, at the level of the synapse. This alteration is accompanied by a accumulation of synaptic vesicles, indicating a disruption of vesicular traffic.
The researchers also identified a mechanism that could explain these abnormalities. They show that a dysfunction in intracellular trafficking, involving in particular the Rab11 protein, contributes to the toxic effects of isoform 1 of BIN1 on the synapses. In the Drosophila model, the increase in Rab11 activity also helps to prevent some of the observed synaptic transmission defects.
Furthermore, the study reveals that isoform 1 of BIN1 modifies the structure of synapses. Researchers observed a increase in the number of small synaptic buttons, as well as so-called buttons satellitesthat is, those that form ectopically. These results demonstrate a disruption of the organization of connections between neurons.
The toxic effects of isoform 1 of BIN1 observed on the function and structure of synapses in Drosophila, were also confirmed in a mammalian model (preclinical models), thus reinforcing the relevance of the results. They showed that the deleterious effects of BIN1iso1 are only observed when this isoform is overexpressed in the presynaptic compartmentThat is, at the neuron terminal upstream of the synapse that emits the nerve signal. Under these conditions, the connections between neurons are fewer and communication within the neural network is disrupted.
A discovery that opens up new therapeutic avenues
This research highlights the toxicity of BIN1 isoform 1 on the synapses and provide knowledge about the molecular mechanisms through which BIN1 may contribute to the observed neurodegeneration, particularly in Alzheimer's disease. Given the genetic association between the BIN1 gene and this pathology, these results suggest that a specific therapeutic targeting The different isoforms of BIN1 could constitute a promising strategy.
Lambert E, Gelle C, et al. BIN1 gain-of-function in the presynaptic compartment leads to isoform-specific synaptotoxicity. Alzheimers Res Ther. 2026 Jun 3. doi: 10.1186/s13195-026-02103-7. Epub ahead of print. PMID: 42237143.
