Late-onset Alzheimer’s Disease (LOAD) is the most common cause of dementia. AD is characterized by the presence of neurofibrillary tangles and of amyloid plaques, mainly composed of β-amyloid peptides (Aβ). Aβ is generated intracellularly at early endosomes through the sequential cleavage of the amyloid precursor protein (APP) by two proteases, β-secretase (BACE1) and γ-secretase. This process is dependent on both APP and BACE1 endocytic trafficking. The Aβ peptide especially its longer form (Aβ42), is synaptotoxic.
Bridging integrator 1 (BIN1), an endocytic trafficking regulator, was identified through large genome-wide association studies to be the second-most prevalent genetic risk factor for LOAD, with the P318L and K358R mutations in BIN1 having been found in increased frequency amongst AD patients. Moreover, BIN1 knockdown was found to increase Aβ42 generation by accumulating BACE1 at early endosomes. However, how two BIN1 coding mutations lead to AD remains unknown. We hypothesized that these BIN1 mutations alter Aβ homeostasis, thus contributing to the development of LOAD.
Expression of BIN1 P318L, but not of BIN1 K358R, led to an increase in total BIN1, suggesting that the first mutation increases BIN1 gene expression. Moreover, over-expression of mutant BIN1 not only increased Aβ42 accumulation but also altered the site of Aβ42 accumulation. We started investigating the mechanisms involved and found early endosomes with reduced levels of EEA1, a marker of early endosomes, in cells overexpressing BIN1 mutants. Finally, we found increased levels of BACE1 in cells overexpressing P318L, but decreased in cells overexpressing K358R, which suggests that they contribute to the development of AD through different pathways.
In conclusion, our research demonstrates that these SNPs do alter BIN1’s normal functioning and lead to Aβ dyshomeostasis, the predominant model of AD pathogenesis. Nonetheless, the specific pathways whereby these mutations impact the production and/or clearance of Aβ42 still require further investigating
