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Gender differences in Alzheimer’s disease

Aging is considered the most important risk factor for Alzheimer’s disease. Yet, this neurodegenerative disease afflicts elderly women much more frequently than men, even when accounting for longer life expectancy. Studies of the aging human brain also show a difference in the activity of specific genes between men and women – some of which are functionally linked to the molecular pathology of Alzheimer’s. Enrico Glaab, principle investigator of the Biomedical Data Science group of the LCSB, aims to find out how gender-specific biomolecular changes in the human brain contribute to the gender differences in Alzheimer’s disease.

To answer this question, Glaab performed statistical analysis of DNA transcription datasets frompost mortemhuman brains of Alzheimer patients and age-matched healthy controls, as well as healthy individuals from different age groups. The goal was to identify genes that differ substantially in activity between men and women of the older age group and show significant gender-specific alterations in Alzheimer’s patients compared to control subjects. Glaab identified such a gene, ubiquitin-specific peptidase 9 (USP9), which fulfils these criteria. USP9 phosphorylates and thereby regulates a protein, Microtubule-Associated Protein Tau (MAPT), which is associated with Alzheimer’s disease. The expression patterns of USP9 and MAPT are highly correlated.

To investigate functional links between USP9 and MAPT and their role in Alzheimer’s disease, Glaab collaborates with colleagues from the Experimental Neurobiology group and the Chemical Biology group at the LCSB. They study the role of USP9 first in cell cultures, then in zebrafish and mouse models. Computational analysis allowed the researchers to narrow down the candidate genes to USP9, substantially reducing the number of animals needed for the investigation. Once work in cell culture and zebrafish makes clear that inactivating USP9 reduces MAPT expression, the researchers can go on to study USP9 activity in a new mouse model for Alzheimer’s disease. Since changes in MAPT expression are a common molecular hallmark of Alzheimer’s and related diseases, potential key regulators of MAPT activity such as USP9 could be further studied as a target for new therapies.

Glaab’s research shows how LCSB researchers choose the most appropriate research method to answer a given scientific questions. Taking different steps from human data sets via computer models and cell cultures to zebrafish and mice allows formulating strong hypothesis such that researchers only preform animal experiments if no other research method could answer the scientific question.

Glaab’s project proposal won the Global NeuroDiscovery Challenge of the US Geoffrey Beene Foundation in 2013.