2023 Alzheimer's Association Research Fellowship (AARF)

Presenilin2 in Endolysosomal Homeostasis: A Focus on Membrane Contact Sites

How may a protein linked to beta-amyloid production assist in the development of amyloid plaques in Alzheimer’s?

Céline Vrancx, Ph.D.
Flanders Institute for Biotechnology, VIB
Leuven, Belgium

Background

Beta-amyloid accumulates to form plaques, one of the hallmark brain changes observed in Alzheimer’s. It is produced from a larger protein called amyloid precursor protein (APP). Presenilin (PSEN) proteins are involved in the creation of beta-amyloid by cutting APP into smaller fragments. People with variations in the genes for presenilin, the PSEN1 and PSEN2 genes, develop an early-onset form of Alzheimer’s called familial Alzheimer’s disease (FAD). FAD involves memory loss and other cognitive symptoms, usually beginning in one’s forties. Because PSEN1 protein has many more variations linked to Alzheimer’s, it has received more interest from researchers than PSEN2. As a result, knowledge of PSEN2’s role in dementia risk is more limited. 

To reduce this knowledge gap, Dr. Céline Vrancx and colleagues have been studying the biological mechanisms that may link PSEN2 and Alzheimer’s disease. They observed that the protein may impact compartments inside cells called endosomes and lysosomes. Endosomes transport unwanted cell waste (including disease-related beta-amyloid) to lysosomes, where the waste is degraded and disposed. Dr. Vrancx’s team found that PSEN2 is located near places where endosomes and lysosomes come in contact (places called “membrane contact sites”). These findings suggest that PSEN2 normally helps maintain the waste-clearing functions of endosomes and lysosomes (the endolysosomal system); and that disease-related PSEN2 variations may have the opposite effect – preventing the disposal of beta-amyloid and promoting the development of amyloid plaques in Alzheimer’s. In addition, the researchers found that abnormal PSEN2 may prevent amyloid clearance in another way – by hindering immune cells in the brain called microglia from “engulfing” unwanted amyloid molecules.

Research Plan

Dr. Vrancx and colleagues will now devote their grant to a larger study of how PSEN2 variations and amyloid clearance in Alzheimer’s. For this effort, they will use nerve cells and microglia developed from a specialized type of stem cells collected from adult human tissue called induced pluripotent stem cells (iPSCs). iPSCs are adult human skin cells that can be “reprogrammed” into any type of cell in the human body and grown in laboratory dishes. The iPSCs in this study will be collected from cells of individuals with and without FAD-related PSEN2 variations. First, the investigators will clarify how PSEN2 variations disrupt protein-clearing functions of the endolysosomal system and of microglia. Next, they will examine in more detail the “environment” that surrounds PSEN2 at membrane contact sites. A greater understanding of this environment can identify proteins and other novel factors that may work with PSEN2 to promote Alzheimer’s-related brain changes.   

Impact

Results from this study will shed new light on the mechanisms underlying PSEN2’s role in beta-amyloid accumulation. They could also lead to novel dementia therapies that target PSEN2 variations.