Alzheimer’s disease (AD) is the most prevalent form of dementia and a leading cause of disability and death in older adults. In Europe alone, it currently affects more than 14 million people — a number projected to rise significantly as the population ages — making AD not only a pressing medical challenge, but also a growing social and economic crisis. Despite major advances in research, there is still no effective treatment to prevent, halt, or reverse the course of the disease. One of the defining biological features of AD is the accumulation of toxic amyloid-beta plaques in the brain, which are thought to interfere with communication between brain cells and trigger damaging inflammation. While reducing amyloid-beta levels has been a central goal of therapy development, it remains unclear whether this alone is sufficient to improve symptoms or slow disease progression.
Recent advances in human genetics have brought new insights into the molecular underpinnings of AD. Large-scale genome-wide association studies (GWAS) have identified novel genetic risk factors, many of which influence the function of microglia—the brain’s resident immune cells responsible for clearing toxic proteins such as amyloid-beta and other cellular waste, thereby maintaining neural health. Among these novel genetic risk factors is TSPAN14, a gene whose increased expression has been associated with a higher risk of developing AD. Interestingly, certain naturally occurring forms of the gene, which lead to lower production of the TSPAN14 protein and therefore reduce its activity, appear to protect against the disease. However, the biological mechanisms behind these genetic links remain largely unexplored.
The TSPAN14-AD project, "Functional analysis of TSPAN14 as a genetic risk factor for Alzheimer's disease", was designed to address this gap in our knowledge. The aim of the project is to gain a better understanding of the physiological role of TSPAN14 in the brain and how it may contribute to the development of AD. Specifically, the project focuses on TSPAN14’s role in microglia and their activity. It investigates how TSPAN14 influences ADAM10, a protease involved in cleaving multiple transmembrane proteins in the brain, including the AD-related proteins APP and TREM2. Emerging evidence suggests that TSPAN14 directs ADAM10’s activity in a cell-type-specific manner — for example, by potentially altering TREM2 cleavage in microglia. Since TREM2 plays a critical role in microglial function and immune response, its improper regulation may impair the brain’s ability to clear toxic proteins, thereby accelerating disease progression.
The central hypothesis of the TSPAN14-AD project is that TSPAN14 contributes to AD by altering ADAM10-mediated cleavage of TREM2, ultimately disrupting microglial function and the brain’s ability to remove amyloid-beta plaques. The project follows three key objectives:
1) To confirm GWAS findings that AD-protective TSPAN14 isoforms formed through alternative splicing mechanisms result in reduced TSPAN14 expression
2) To determine whether reduced TSPAN14 expression affects the surface expression of ADAM10 in microglia
3) To assess whether reduced TSPAN14 expression decreases TREM2 cleavage thereby enhancing the phagocytic function of microglia
By dissecting how TSPAN14 contributes to AD at the molecular level, this research aims to uncover new potential targets for treatment that go beyond traditional plaque-based approaches. The findings could pave the way for more precise, cell-type-specific interventions aimed at improving microglial function and slowing or preventing the onset of AD. This project contributes to the broader EU efforts to address major health challenges by advancing neurodegenerative disease research. It also highlights the growing importance of integrating genetics, cellular neuroscience, and immune system research, helping shape future strategies for AD prevention and treatment.
