Molecular and cellular mechanisms in the phosphorylation of the amyloid beta-peptide and their pathophysiological relevance

• Applicant: Professor Dr. Jochen Walter, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2009
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 115301661

Alzheimer’s disease (AD) is characterized by the combined occurrence of intraneuronal aggregates (neurofibrillary tangles) and extracellular deposits in form of amyloid plaques. Neurofibrillary tangles consist of the microtubule-associated protein tau, while plaques contain aggregated amyloid ß-peptides (Aß).Aß derives from the proteolytic processing of the amyloid precursor protein (APP). Accumulating evidence suggest a critical role of Aß in the initiation of AD pathogenesis, because all mutations identified so far to cause early onset familial forms of AD, commonly increase the generation or aggregation of Aß. However, such mutations are very rare and account for less than five per cent of all AD cases. The mechanisms causing the much more common late onset forms of AD are largely unclear.In the course of this project, we could identify novel post-translational modifications of Aß by phosphorylation. Phosphorylated Aß variants were detected in brains of transgenic mice as well as human AD patients. We also identified two distinct phosphorylation sites and the respective putative protein kinases. Interestingly, the phosphorylation strongly promotes the aggregation of Aß and its neurotoxicity, and is associated with the progression of AD. Together, these data indicate an important role of Aß phosphorylation in the pathogenesis of AD. The main aims of the project are the elucidation of basic molecular mechanisms in the phosphorylation of Aß, and the characterization of functional implications in the pathogenesis of AD. In particular, the involvement of phosphorylation reaction at the cell surface, in extracellular fluids and intracellular compartments will be investigated. In addition, phosphorylated Aß variants in brain tissue will be characterized by mass spectrometry. Finally, specific transgenic mouse models will be generated in order to characterize the role of Aß phosphorylation in vivo. Together, the project could not only provide insight into basic mechanisms of AD pathogenesis, but also holds potential for future translation into therapeutic intervention and diagnosis.

• DFG Programme: Research Grants