Identification of brain cell-type specific gene-regulatory networks in PS1 E280A Familial Alzheimer Disease patients

• Applicant: Dr. Diego Sepulveda-Falla
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Bioinformatics and Theoretical Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458854216

Even though Familial Alzheimer’s disease (FAD) represents less than 1% of Alzheimer’s disease cases, it is considered as the ideal model for understanding disease development and its biological basis. The largest family suffering from FAD, sharing a single mutation in the Presenilin 1 gene (PSEN1 E280A), resides in Colombia, South America and includes more than 1200 mutation carriers. As of today, more than 120 brains have been donated by PSEN1 E280A carriers and family members. These brains constitute an invaluable resource in Alzheimer’s research. They are as homogeneous as a human sample can be, sharing a common genetic background and a common environment, while presenting wide variability in clinical presentation and resulting brain pathological features. During the last decades we have been characterizing these patients and these brains and we have identified that the disease starts at least one decade before dementia, that PSEN1 E280A patients with specific symptoms show similar cerebellar and mitochondrial damage; and that other genetic variants can modify the course of the disease, by for instance, delaying its onset. Also, from the pathological findings in these brains we have identified new cellular mechanisms in which PSEN1 mutations can affect cells, leading them to death. The wide clinical and pathological heterogeneity found in this FAD large cohort is, in certain way, a microcosmos of the larger variability found in sporadic Alzheimer’s disease. This project aims to understand the biological causes of this heterogeneity by performing single nuclei RNA sequencing in a large sample of PSEN1 E280A brains that present all the variety of symptoms and clinical course found in this population. With this we will identify which types of brain cells, between neurons, astrocytes, microglia and oligodendrocytes, are more affected by the PSEN1 E280A mutation, and how this specific cell pathology correlates with clinical history and presentation by using state of the art high throughput data analysis. The large quantity of data obtained will be shared freely with the Alzheimer’s scientific community, allowing the generation of even more interpretations of the findings and of possible personalized medicine strategies for AD treatment.

• DFG Programme: Research Grants