Unmasking cellular and molecular networks encoding risk and resilience in Alzheimer’s disease

Project Information

AD_AGING_AND_GENDER

Grant agreement ID: 853409

DOI

10.3030/853409

EC signature date 5 May 2020

Start date 1 June 2020

End date 30 September 2026

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 500 000,00

EU contribution

€ 1 500 000,00

Coordinated by

THE HEBREW UNIVERSITY OF JERUSALEM
Israel

Periodic Reporting for period 3 - AD_AGING_AND_GENDER (Unmasking cellular and molecular networks encoding risk and resilience in Alzheimer’s disease)

Reporting period: 2023-06-01 to 2024-11-30

Summary of the context and overall objectives of the project

Alzheimer’s disease is emerging as a crucial problem in our society, raising the need for new therapeutic targets. One of the challenges in the study of the disease is that the course of the disease is highly variable across individuals, due to multiple different risk factors, including age and sex. Moreover, the aging process has overlapping molecular features with Alzheimer’s disease that might be masking the mechanism of disease. We hypothesized that age- and sex- dependent cellular and molecular changes in the brain are key drivers of the development of Alzheimer’s disease and of the memory impairment, and that the dynamics of this cellular cascade in the brain, determines the risk and resilience levels of individuals. In this project we aim to expand the traditional resolution in the study of Alzheimer’s disease from tissues to entire cellular environments, and to untangle overlapping molecular signatures of sex and aging, in order to unmask the true molecular mechanism of Alzheimer’s. The complexity of the brain tissue has been hampering the investigation of the different brain cells and their role in Alzheimer’s disease. Here, we are harnessing recent complementary technological advancements - in genomics: mapping RNA molecules with single cell resolution, in imaging: multiplexing imaging of hundreds of RNA molecules, as well as in machine learning and computational modeling.
Our specific goals for this project are to: 1) Map brain cells, molecular profiles and cellular environments that are unique to Alzheimer’s disease brains compared to healthy aging. 2) Chart the cellular cascade that leads to disease and how it differs from healthy aging. 3) Predict key cells and molecules that drive the increased risk for Alzheimer’s disease in women compared to men, and the key cells and molecules that drive cognitive resilience with age. 4) Investigate the key driver molecules to uncover the mechanism of disease and new drug targets. Overall, our innovative proposal has the potential to advance us toward novel and more effective therapeutic targets for Alzheimer’s disease.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In this project we are building cellular maps of the aged brain and charting the cascade of events underlying Alzheimer’s disease and aging in human brains and in mouse model, and also uncovering the basis for the differences in the risk for the disease between men and women. So far, our work has led to several important insights. Our maps demonstrated for the first time that the entire cellular environment of the brain changes along the development of Alzheimer’s disease and thus might play a key role in the progression of the disease. These findings also transformed our view of the disease, as a disease of the whole brain, and expanded beyond previous research in the Alzheimer’s field that traditionally focused on damage to neuronal cells or the effect of a single cell type. Another major breakthrough in our work, is showing that Alzheimer’s disease can be distinguished from other forms of aging at a cellular and molecular level from a very early stage.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

We have provided a cellular foundation for a new perspective of Alzheimer’s disease pathophysiology in which a pathologic community of cells will become the true target of therapeutic development. We aim to further deepen and expand this view as the project progresses. Given the planned large-scale data generation, detailed maps and dynamic analysis, our work is expected to have therapeutic implications that could advance us toward effective personalized prevention therapies for Alzheimer disease and other aging brain pathologies.

overview-small-forb1.png