Investigating lysosomal dysfunction and exocytosis in Alzheimer's disease
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder that typically follows an insidious onset and a gradual decline in cognitive function. As there is no cure for AD, therapeutic approaches rely on medications that primarily alleviate symptoms. With an aging global population, ongoing research is needed to better understand the pathophysiological mechanisms underlying this cruel disease and explore potential therapies to slow or halt its progression. AD is associated with the accumulation of abnormally aggregated amyloid beta (Aβ) and hyperphosphorylated tau. Lysosomal dysfunction has long been linked to AD, whereby the failure of lysosomes results in an inability to digest pathological Aβ and tau.
This thesis explored lysosomal dysfunction in AD by examining lysosomal exocytosis as a pathway for Aβ secretion from neurons and by evaluating ambroxol as a potential therapeutic agent to enhance lysosomal function. In live neurons derived from AD patients, total internal reflection fluorescence microscopy captured lysosomes docking and fusing with the plasma membrane, leading to the release of intracellular Aβ. Silencing of molecular machinery involved in lysosomal exocytosis significantly reduced Aβ secretion. Additionally, the repurposing of the mucolytic agent ambroxol as a novel treatment for AD was studied for its ability to enhance lysosomal function. Ambroxol treatment resulted in an increase in various lysosomal genes and proteins in cultured neurons and in the 3xTg mouse model of AD. Importantly, there was a corresponding reduction in brain levels of Aβ and tau in mice fed with ambroxol.
These findings provide further insight into the contribution of lysosomal dysfunction to the pathogenesis of AD. Specifically, lysosomal exocytosis serves as a pathway of Aβ release from neurons, and ambroxol treatment reduces Aβ and tau pathology by upregulating lysosomal activity. Ultimately, understanding the role of the lysosome in AD unveils critical pathways for targeted therapies aimed at enhancing lysosomal function and clearing toxic aggregates.