ADAMTS proteases in Alzheimer’s disease

• Applicants: Professor Dr. Sascha Weggen; Professor Dr. Oliver Wirths
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 494911640

The accumulation of Abeta peptides in the brain is a critical step in the pathogenesis of Alzheimer’s disease (AD). In autopsy brain samples from AD patients, a large fraction of the insoluble Abeta peptides are truncated at the N-terminus, with Abeta4-x peptides being particularly abundant. Recently, we demonstrated that Abeta4-x peptides are generated through cleavage of the amyloid precursor protein (APP) by the secreted metalloprotease ADAMTS4. ADAMTS4 is exclusively expressed in oligodendrocytes, and white matter structures in an AD mouse model showed abundant immunoreactivity for Abeta4-x peptides, supporting the hypothesis that these toxic N-truncated Abeta species might contribute to white matter abnormalities in AD. In this application, we have three major objectives to answer fundamental questions about the role of ADAMTS proteases and N-truncated Abeta4-x peptides in AD. Our first objective is to investigate the pathological impact of ADAMTS4 and N-truncated Abeta4-x peptides on white matter integrity and function. Based on novel preliminary data indicating that white matter structures are altered in the 5xFAD mouse model of AD, we will comprehensively study white matter integrity, myelination, and functional outcomes in the brain and spinal cord of 5xFAD and 5xFAD/ADAMTS4-/- mice, as well as in newly generated transgenic mice in which human APP is overexpressed under control of an oligodendrocyte-specific promotor. Our second objective is to gain a detailed understanding of the molecular interaction of ADAMTS proteases with the proteins of the APP gene family. We propose that low density lipoprotein receptor-related protein 1 (LRP1) functions as a scaffold protein and mediates the interaction between ADAMTS4 and APP. In addition, we will explore proteolytic processing of the APP homologs APLP1 and APLP2 by ADAMTS4, and perform an unbiased proteomics screen for novel ADAMTS4 substrates. Our third objective is to study a second homologous protease of the ADAMTS family whose expression pattern in the murine brain is different from ADAMTS4 with prominent expression in astrocytes. We will determine the expression pattern of this ADAMTS protease in the human brain, and we will study how it affects APP processing and Abeta4-x peptide generation in established cell lines and in primary astrocytes. Taken together, our studies aim to establish a firm mechanistic explanation for the recent genetic association of the ADAMTS protease family with AD risk, and to provide alternative and druggable targets for therapeutic intervention.

• DFG Programme: Research Grants