2018 Alzheimer's Association Research Fellowship (AARF)

New neuronal models for intracellular toxic Aß accumulation

Are changes to the brain's waste protein clearance mechanism linked to early brain changes in Alzheimer's?

Marine Bretou, Ph.D.
Vlaams Institut voor Biotechnologie
Flanders, Belgium

Background

Beta-amyloid is a protein fragment that accumulates into amyloid plaques, a characteristic feature of Alzheimer's. To date it is unclear whether plaques are a cause or a consequence of Alzheimer's. Thus, many researchers are studying how beta-amyloid accumulates in the early stages of the disorder — before the development of plaques. Identifying the mechanisms of early clumping may prove vital in detecting the onset of Alzheimer's beta-amyloid

Several studies suggest that one of the early disease-related changes in the brain involves damage to the nerve cells that are responsible for clearing the other unwanted particles called the endolysosomal system. The impairment of this mechanism is thought to play an important role in the early clumping of toxic amyloid molecules. While scientists are still investigating the nature of this role, past studies suggest that a protein called Presenilin 2 (PSEN2) could be involved. This protein is linked to the waste clearance system and is also essential in producing the beta-amyloid protein fragment from its parent molecule. In preliminary research with cultured brain cells, Dr. Marine Bretou and colleagues found that abnormal PSEN2 was a major source of toxic amyloid production.

Research Plan

Dr. Bretou and her team will assess how early beta-amyloid clumping may disable the waste clearance system and contribute to Alzheimer's. First, the researchers will modify specialized stem cells using a novel "gene editing" technique to produce brain cells that contain the human protein Presenilin 2. They will then test how beta-amyloid accumulates in these cells and forms clumps that could affect waste protein clearance activity. Using these results the investigators will test how beta-amyloid or clearance changes may lead to brain cell dysfunction and damage.

Impact

The results of this project could reveal novel underlying mechanics of early-stage brain cell dysfunction in Alzheimer's and identify possible novel therapy development.