2023 Alzheimer’s Association Leveraging Model & Data Resources to Advance Alzheimer’s and Dementia Discovery Program (ALZDISCOVERY)

Dissecting Tau Spreading Using Multi-Omics and Novel Mouse Models of AD

How do proteins that interact with tau promote the formation of tau clumps in the Alzheimer’s brain?

Cristian Lasagna Reeves, Ph.D.
Indiana University
Indianapolis, IN - United States

Background

Tau is a protein that helps maintain the structure of brain cells. In Alzheimer’s and other brain diseases called tauopathies, the shape of tau protein becomes modified or “misfolded,” a change that may contribute to tau tangles (a hallmark of these diseases) and subsequent nerve cell damage. However, the biological mechanisms behind how tau accumulates and moves through the brain is not fully understood. One of the suggested models is that pieces of tau (called tau seeds) can be released from a nerve cell and then taken up by nearby cells. The seeds then promote tau tangle development in new cells – eventually leading to abnormal tau spread throughout the brain. Research also suggests that other proteins may interact with tau seeds to promote this tau “spreading.” 

In initial studies with mice engineered to develop tauopathies, Dr. Cristian Lasagna Reeves and colleagues identified a protein called bassoon (BSN) that interacts with tau seeds. They observed that when levels of BSN were reduced in the mice, the animals developed fewer tau tangles and less tau-related behavioral impairment. In addition, after analyzing brain samples of individuals who had Alzheimer’s, the researchers identified other proteins that interact with tau seeds and may relate to tau spreading.

Research Plan

Dr. Lasagna Reeves and colleagues will now examine the brains of humans and novel Alzheimer’s-like mice using advanced computational methods known as “multi-omics” to expand their earlier findings. Specifically, the researchers will combine proteomics (the study of the structure and functions of proteins made by cells) and transcriptomics (the study of how gene activity is turned “on” or “off” within a cell), along with an analysis of the tau seed interactome (or all the proteins that interact with tau seeds). Using these methods, they will examine how a variety of proteins interact with tau seeds in ways that promote disease, and whether some of the proteins can be used as targets for dementia therapy.

Impact

Results from this project could refine our understanding of the mechanisms underlying tau’s role in Alzheimer’s. They could also lead to novel therapies that target protein interactions linked to tau tangles.