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2023 Endolysosomal Activity in Alzheimer’s (E2A)

Identification of retromer modifiers by arrayed genome-wide perturbation

What mechanisms contribute to impaired “waste disposal” in Alzheimer’s?

Adriano Aguzzi, M.D.
University of Zurich
Zurich, Switzerland


Lysosomes are specialized compartments inside brain cells that help degrade and dispose of a cell’s waste. Studies have shown that lysosomes may often be damaged in brain diseases, causing nerve cells in the brain to lose their ability to clear waste effectively. This inability to clear waste could be associated with the accumulation of beta amyloid plaques and tau tangles, two of the hallmark brain changes in Alzheimer’s.  

Research has shown that a specific protein called a “retromer” may be responsible for impaired waste disposal in Alzheimer’s. However, the mechanisms underpinning this are unclear.

Research Plan

Dr. Adriano Aguzzi and colleagues will examine the mechanisms by which loss of retromer activity impairs waste disposal. They will do this by studying which genes are turned “on” or “off” in cells that have high or low retromer activity. Next, they will focus on the genes that are turned “on” in cells with low retromer activity. They will use a gene editing system called CRISPR to then turn “off” these same genes and study whether waste disposal is restored in cells.


If successful, the results of this study could reveal new mechanisms that contribute to impaired waste disposal systems in Alzheimer’s. The findings will also identify potential new targets to develop Alzheimer’s treatments.

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