Proteasomal degradation of toxic intracellular amyloid-beta protein by nanobody-enabled proximity to ubiquitin ligase

The amyloid-beta (A) protein arises from the sequential proteolytic cleavage of A precursor protein (APP). The accumulation of A oligomers has been regarded as the causal factor of Alzheimers disease (AD).

Basal metabolic production of the A peptide is typical in healthy people, and its production rate is normally lower than its rate of clearance.

In AD, the uncontrolled accumulation of toxic forms of A stemming from problems in its clearance and degradation results in memory loss, chronic neuroinflammation and neurodegeneration.

AD is a leading cause of disability and death both in Europe and the world, and currently has no cure or clinically-proven disease-modifying therapies.

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.

My project proposes a radically novel approach in the AD field of utilizing the bodys cellular waste disposal system to selectively degrade A peptide, the causative agent of AD.

This is in sharp contrast to the current approach of immunization against the A peptide, which has repeatedly failed to yield any cure or disease-modifying therapies for AD.This project will aim to identify the specific cytotoxic A peptides responsible for neuroinflammation and neurodegeneration in human induced pluripotent stem cells and target these peptides for degradation by the ubiquitin proteasome system.

Emphasis will be on the cytotoxic A peptides of intracellular origin as emerging targets in AD.

This research will be conducted at the University of Helsinki, Finland, followed by a non-academic placement at Roche Diagnostics GmbH.