Periodic Reporting for period 1 - Protambbody (Proteasomal degradation of toxic intracellular amyloid-beta protein by nanobody-enabled proximity to ubiquitin ligase)
Reporting period: 2023-01-01 to 2025-06-30
Alzheimer’s disease (AD) is the most prevalent form of dementia as well as the most common neurodegenerative disorder affecting the general public in both Europe and the world. It is also a major cause of disability and death especially in the elderly and currently has no cure. There are over 10 million new cases of dementia each year worldwide (up to 80% of which are due to AD), implying one new case every 3.2 seconds. In Europe, about 10 million people currently suffer from this disease and about 50 million in the world; with these estimates projected to double by 2050. Thus, the identification of novel disease-modifying therapies has become very critical to eradicating AD from Europe and the world.
The disease is believed to be caused by the accumulation of a protein called amyloid beta (Aβ) in the brain. Most clinical trials of therapeutic interventions for AD have failed due to a lack of effective models and an inadequate understanding of the mechanisms underlying the disease process. Importantly, because the etiology of AD is unknown, it is currently impossible to model it appropriately using the popular transgenic models that entail genetic manipulations. Thus, the Protambbody project proposes to model Aβ-associated AD pathology in vitro using human neurons differentiated from induced pluripotent stems cells (iPSCs) reprogrammed from somatic cells of adult human subjects suffering from AD. Using these human iPSC-derived brain cells, Protambbody was designed to investigate a key cellular waste disposal machinery called the ubiquitin proteasome system (UPS) in AD and further manipulate this system to degrade Aβ aggregates being the causative agent of AD.
The disease is believed to be caused by the accumulation of a protein called amyloid beta (Aβ) in the brain. Most clinical trials of therapeutic interventions for AD have failed due to a lack of effective models and an inadequate understanding of the mechanisms underlying the disease process. Importantly, because the etiology of AD is unknown, it is currently impossible to model it appropriately using the popular transgenic models that entail genetic manipulations. Thus, the Protambbody project proposes to model Aβ-associated AD pathology in vitro using human neurons differentiated from induced pluripotent stems cells (iPSCs) reprogrammed from somatic cells of adult human subjects suffering from AD. Using these human iPSC-derived brain cells, Protambbody was designed to investigate a key cellular waste disposal machinery called the ubiquitin proteasome system (UPS) in AD and further manipulate this system to degrade Aβ aggregates being the causative agent of AD.
Protambbody successfully generated human iPSC-derived neurons expressing key markers of the cortical layer and displayed increased Aβ in the AD compared to the control group.
Investigation of the UPS revealed a dynamic change in the composition of the proteasome subtypes between the healthy control neurons and the AD neurons as a possible compensatory response to increased neuronal Aβ levels in human levels.