Amyloid plaques are often observed in the brain of patients with dementia but their direct contribution to neuronal death is contested. Amyloid plaques are formed by the aggregation of secreted amyloid-ß peptides which are produced intracellularly by the proteolytic processing of the amyloid precursor protein (APP) by the membrane-bound proteases β-secretase (BACE1) and γ-secretase. Defects in membrane trafficking can lead to neurodegenerative diseases and the intracellularly accumulation of amyloid-ß is neurotoxic; however, the molecular and cellular pathways responsible for intracellular amyloid-ß accumulation and neuronal damage is poorly defined.
In our research, we are using advanced microscopy and biochemical tools to understand the trafficking itinerary and regulators of the transmembrane proteins APP and BACE1 to reveal the dynamic chronology of molecular events resulting in amyloid-ß accumulation and the initiation of neurodegeneration, using HeLa cells, primary mouse neurons and human iPSC-derived neurons.
Using super-resolution and live-cell imaging, we have shown that APP and its secretase, BACE1, are partitioned in the early secretory pathway, and that this partitioning is critical to regulate APP processing and amyloid-ß production1. Moreover, we established a temporal and spatial analysis of the trafficking and processing of wild-type APP and disease related APP mutants along the secretory pathway, using the Retention Using Selective Hooks (RUSH) combined with biochemistry methods2. Our analysis revealed the Golgi apparatus as the major processing site for the pathogenic Swedish APP mutation in contrast to endosomes for wild-type APP2. The Golgi apparatus is a central trafficking hub and Golgi fragmentation has emerged as an early event and hallmark of familial and sporadic Alzheimer’s disease. Following our characterization of the secretory network in human iPSC-derived neurons, we identified for the first time highly dynamic dendritic Golgi in human neurons3.
These findings are highly relevant to understand the molecular basis of amyloid-β production and Alzheimer’s disease. We are now exploring the nexus between cargoes trafficking, neuronal activity and Golgi fragmentation in healthy and neurodegenerative disease-associated human iPSC-derived neurons to define the downstream pathways impacting neuronal function.
References:
1 Fourriere, L., Cho, E. H. J., & Gleeson, P. A. (2022). Traffic, 23(3), 158-173. DOI: 10.1111/tra.12831
2 Wang, J., Gleeson, P. A., & Fourriere, L. (2024). Traffic, 25(3), e12932. DOI:10.1111/tra.12932
3 Wang, J., Daniszewski, M., Hao, M. M., Hernández, D., Pébay, A., Gleeson, P. A., & Fourriere, L. (2023). Cell Reports, 42(7). DOI:10.1016/j.celrep.2023.112709