Regulation of amyloid precursor protein processing pathway by β-secretase and its impact on Alzheimer's disease physiopathology

On Tuesday November the 12th 2024, Karina VARGAS will defend her thesis "Regulation of amyloid precursor protein processing pathway by β-secretase and its impact on Alzheimer's disease physiopathology".

This thesis has been directed by Alain BUISSSON from the "Neuropathologies and Synaptic Dysfunctions" team of the GIN.

Jury members

- Magalie Lecourtois, CNRS Paris Normandie, Rapporteure
- Lucia Chavez Gutierrez Vib-ku, Leuven Center for Brain and Disease Research, Rapporteure
- Santiago Rivera, CNRS Provence et Corse, Examinateur
- Alain Buisson, GIN, Université Grenoble Alpes, Directeur de thèse
- Sabrina Boulet, Université Grenoble Alpes, Examinateure

Abstract

Alzheimer's disease (AD) is a predominant neurodegenerative disorder marked by cognitive decline and synaptic dysfunction. The distinctive neuropathological hallmark is the accumulation of amyloid plaques in the brain. The intricate interplay of amyloid precursor protein (APP) processing, orchestrated by β-secretase (BACE1) and γ-secretase, assumes a pivotal role in AD pathophysiology by generating amyloid-beta (Aβ) peptides. Our investigation explores the impact of Aβ production on synaptic density and morphology within primary cortical neurons. We employ genetic manipulations and pharmacological interventions to demonstrate that alterations in APP processing significantly contribute to dendritic spine density alterations. Further investigations employing APP knockout neurons and specific mutations reveal that Aβ production is crucial for regulating synaptic density. Pharmacological inhibition of BACE1 and γ-secretase rescues the synaptic phenotype induced by the amyloidogenic pathway, highlighting the direct involvement of Aβ in synaptic alterations. Additionally, our study explores the influence of synaptic activity on APP processing, revealing that increased neuronal activity promotes BACE1 cleavage of APP, leading to Aβ production. Our research employs various techniques, including live-cell imaging, Western blotting, and Electron Microscopy, to characterize the dynamic interplay between APP processing and synaptic activity. Our results suggest a possible translocation of APP into early endosomes upon synaptic activation, a phenomenon mitigated by BACE1 inhibition. Electron microscopy images exhibit altered vesicular compartments in BACE1 inhibitor-treated neurons, reminiscent of APP processing-related phenotypes observed in AD mice models. We aim to elucidate the intricate relationship between APP processing, Aβ production, and synaptic plasticity. These findings contribute valuable insights into the molecular mechanisms underlying AD pathophysiology and offer potential therapeutic targets.