Pinning Down How Alzheimer's Risk Gene BIN1 Controls Brain Immune Responses

The aim of this project is to examine how a risk protein affects brain immune cell response to amyloid-beta in Alzheimer’s disease.

The brain relies on protective immune cells called microglia, which respond to disease processes in the brain, including in Alzheimer’s. To communicate with other cells, microglia package proteins into small structures that can move between cells. One protein they include in these packages is BIN1, which supports successful receipt of the messages by the target cells and has been implicated in Alzheimer’s disease.

In this project, Ari Sudwarts, PhD, aims to identify the key actors involved with BIN1 as it operates in microglia and how these packaged messages affect target cells. One cutting-edge tool Dr. Sudwarts will use can highlight the proteins that interact with BIN1. It relies on an enzyme fused to BIN1 that immediately tags any protein that gets near it. For this project, the researchers will use a virus to introduce the fused BIN1 into microglia. By tagging the interacting proteins, the team will be able to track their behavior in microglia that have been provoked into action and study how these proteins affect messages to target cells.

Their novel approach combining these tools to track protein interactions in living cells is expected to be applicable to many other genes and cell types. The researchers expect their work to result in a useful molecular tool for studying the link between risk genes and specific cell types in Alzheimer’s and other diseases.

The two central technologies – proximity labelling (by TurboID enzyme fusion) and the virus method for expressing in brain microglia – are relatively new. The combination of these two techniques will be one of the first endeavours to identify the interactome of an Alzheimer’s risk gene in in vivo microglia.

The use of TurboID to identify target cells is a novel approach, never undertaken before, providing a first-time ever insight into the effects of an Alzheimer’s risk gene on other cell types; this approach may be used in countless future studies of other genes and other cell-types.

By identifying BIN1 interactors in microglia – particularly surface receptors – potential targets for drug development will be identified. The viral mechanism to target brain microglia can be applied to other/future models of Alzheimer’s pathology, validating or refining the project’s findings. The use of this system to identify non-microglial target cells represents a proof-of-concept study, which may be applied to investigate signalling from other cell-types, and to research on other diseases.