Abstract
The Bridging Integrator 1 (BIN1) gene is a major susceptibility gene for Alzheimer’s disease (AD). Deciphering its pathophysiological role is challenging due to its numerous isoforms. Here we observed in Drosophila that human BIN1 isoform1 (BIN1iso1) overexpression, contrary to human BIN1 isoform8 (BIN1iso8) and human BIN1 isoform9 (BIN1iso9), induced an accumulation of endosomal vesicles and neurodegeneration. Systematic search for endosome regulators able to prevent BIN1iso1-induced neurodegeneration indicated that a defect at the early endosome level is responsible for the neurodegeneration. In human induced neurons (hiNs) and cerebral organoids, BIN1 knock-out resulted in the narrowing of early endosomes. This phenotype was rescued by BIN1iso1 but not BIN1iso9 expression. Finally, BIN1iso1 overexpression also led to an increase in the size of early endosomes and neurodegeneration in hiNs. Altogether, our data demonstrate that the AD susceptibility gene BIN1, and especially BIN1iso1, contributes to early-endosome size deregulation, which is an early pathophysiological hallmark of AD pathology.
Highlights
Alzheimer’s disease is the most common form of dementia, characterized by two main cerebral lesions: the extracellular aggregation of the amyloid beta peptide (Aβ) into senile plaques and the intracellular aggregation of phosphorylated Tau into tangles
We obtained transgenic lines expressing identical basal level of Bridging Integrator 1 (BIN1) isoforms with two additional BIN1iso1 and BIN1iso9 lines expressing high BIN1 levels that we used for dose-dependent effects (Additional file 1 and Additional file 2: Fig. S1)
We tested if the expression of muscle human BIN1iso8 could restore the locomotor performance of dAmph deficient adult transgenic flies assessed in the so-called climbing test
Summary
Alzheimer’s disease is the most common form of dementia, characterized by two main cerebral lesions: the extracellular aggregation of the amyloid beta peptide (Aβ) into senile plaques and the intracellular aggregation of phosphorylated Tau into tangles. BIN1 encodes at least 20 exons subject to extensive differential splicing, generating multiple isoforms with different tissue distributions [49]. All BIN1 isoforms possess the N terminal BIN1/Amphiphysin/Rvs (BAR) domain, involved in membrane curvature sensing and induction, the C-terminal MYC-Binding Domain (MBD) and the C-terminal SH3 domain, a protein–protein interaction domain that recognizes proline-rich domains like the one in Tau [49, 59]. Muscle-specific isoforms contain a phosphoinositide-interacting (PI) domain, whereas brain-specific BIN1 isoforms are mainly characterized by inclusion of exons encoding a Clathrin and Adaptor Protein-2 binding (CLAP) domain involved in endocytosis and intracellular trafficking. BIN1 expression is mainly observed in oligodendrocytes, microglial cells and neurons [1, 41, 52]. While neurons express high molecular weight isoforms including BIN1iso, glial cells express lower molecular weight isoforms such as BIN1iso9 [52, 69]
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