The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects

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.

The Alzheimer’s disease risk gene BIN1 modulates neural network activity via the regulation of L-type calcium channel expression in human-induced neurons

“…2E-H). In agreement with our previous observations in cerebral organoids (Lambert et al, 2022), we did not detect any significant differences neither in the concentrations of soluble Aβ(1-x) or Aβ(1-42), nor in the intracellular levels of full-length APP and APP CTF-β in BIN1 KO compared to WT hiN cultures in 2D (Sup. Fig.…”

“…Nuclei isolation and Hash-tagging with oligonucleotides steps were realized on ice with pre-cold buffers and centrifugations at 4°C. 6.5-month-old BIN1 WT, HET, and KO organoids were processed as previously (Lambert et al, 2022 Fisherscientific). Isolated nuclei were loaded on a Chromium 10X genomics controller following the manufacturer protocol using the chromium single-cell v3 chemistry and single indexing and the adapted protocol by Biolegend for the HTO library preparation.…”

“…Changes in BIN1 expression have been controversially associated with amyloid precursor protein (APP) processing towards the production of amyloid-beta (Aβ) peptides in cellular models 10,11 . However, we recently showed that BIN1 regulates endocytic trafficking in hiPSC-derived neurons (hiNs), without significantly affecting amyloidogenic APP processing 12 and BIN1 underexpression does not modify amyloid pathology in an AD-like mouse model 13 . A direct interaction between TAU and BIN1 has also been reported 14,15 potentially impacting learning and memory in a Tauopathy mouse model 16 , Tau phosphorylation and propagation in vitro 16–19 or network hyperexcitability in rat hippocampal neurons 19 .…”

NF-κB in neurodegenerative diseases: Recent evidence from human genetics

“…Although the particular pathogenic mechanism linking BIN1 and Tau in AD progression remains unclear, BIN1 may modulate Tau aggregation/oligomer formation in earlier disease stages ( Chapuis et al, 2013 ). In human induced neurons, BIN1-knockout reduced early endosome signaling and overexpression of the AD-relevant isoform of BIN1 (isoform 1) increased the size of early endosomes and led to neurodegeneration ( Lambert et al, 2022 ). The TNFα pathway with linear ubiquitination was also included in the new genetically associated processes within AD patients ( Bellenguez et al, 2022 ).…”

BIN1 knockdown rescues systolic dysfunction in the aging heart

“…In the heart, BIN1 is better known for its role in targeted delivery of CaV1.2 35,36 , t-tubule biogenesis 37 , micro-folding 38 , and maintenance 39 , and in dyad formation 40 . However, in neurons, where there are no t-tubules, BIN1 is known to play a role in mediating endosomal membrane curvature and tubule formation required for cargo exit and recycling from endosomes 41,42 . BIN1 overexpression has been linked to aging and neurodegeneration in the brain [43][44][45] and has been seen to produce endosomal expansion and traffic jams 34,41,42 .…”