The role of microRNA-RNA regulatory networks in neural circuits affected by Alzheimer's disease

• Applicant: Professor Dr. Lars Bertram
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 391523883

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, and is characterized by a progressive loss of memory and cognition ultimately leading to dementia. Cognitive decline is the result of a complex pathophysiology involving the dysfunction of neural circuits. At the same time, the onset, progression and clinical picture of AD is governed by genetic factors that exert molecular effects which are hitherto only poorly characterized. In this joint project between the Universities of Lübeck, Germany, and Wuhan, China, we will combine cutting-edge high-throughput genomics technologies with state-of-the-art in vivo functional modeling to decipher the connection between microRNA-RNA regulatory networks and dysfunction of the entorhinal cortex (EC)-hippocampal (HPC) neural circuit in AD.MicroRNAs (miRNAs) are small, non-coding RNAs that down-regulate RNA expression by specific, complementary binding. Since each miRNA typically targets several different RNAs, regulatory networks emerge. For studying these networks, we will generate genome-wide genetic variant data and next generation sequencing-based transcriptome data on miRNA-RNA binding sites and on the expression of miRNAs as well as other non-coding and coding RNAs. Importantly, all genomics and transcriptomics experiments will be performed on DNA/RNA extracts obtained from approximately 100 fresh frozen human, post-mortem EC brain samples without evidence of dementia. By integrating these data sets with findings from AD genetics studies, we will be able to identify molecular effects that play a primary role in AD pathophysiology rather than being secondary to the disease process itself. In addition to miRNA-mediated regulation, we will generalize our approach to post-transcriptional regulation mediated by RNA-binding proteins. Identified miRNA and RNA candidates will then be assessed in vitro and in vivo using a number of different transgenic mouse models. This will be achieved by manipulating the relevant miRNA/RNA candidates in the EC of 3XTg-AD mice by CRISPR/Cas9 mediated knockdown or Cre-loxp plus virus mediated overexpression and studying their effects on the mouse EC-HPC circuit. In addition, we will explore whether correcting the abnormal expression of the candidate miRNAs can effectively rescue the EC-HPC circuit dysfunction, including memory deficits, Aß deposition, and tauopathy in AD mice.In this joint project, we combine large-scale, brain-derived human genome/transcriptome data with targeted functional in vivo assessments within the EC-HPC neural circuit in mice. As such, the project will shed substantial new light on the dysfunction of post-transcriptional regulatory networks that play significant roles in AD pathogenesis and manifestation.

• DFG Programme: Research Grants
• International Connection: China
• Partner Organisation: National Natural Science Foundation of China
• Cooperation Partner: Professor Ling-Qiang Zhu