Pathogenic role of neuronal p38alpha-MAPK in Alzheimer disease

• Applicant: Privatdozent Dr. Yang Liu
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 283394766

In Alzheimer disease (AD), the key pathogenic molecule, amyloid beta peptide (Abeta), is generated from its precursor protein (APP) after sequential cleavages of beta- and gamma-secretases. A stress-related kinase, p38-MAPK, is highly activated in the AD brain. In preliminary experiments, we observed that deletion of p38alpha-MAPK in neurons using the Cre-Lox technique can reduce cerebral Abeta load in APP-transgenic mice. As a potential mechanism, we have demonstrated that p38alpha-MAPK deficiency enhances autophagy and facilitates BACE1 degradation in cultured neuronal cells. In this proposal, we extend our preliminary study to investigate whether deficiency of p38alpha-MAPK in neurons ameliorates AD-associated pathological changes, i.e. neurodegeneration, Abeta pathology and neuroinflammation in APP-transgenic mice. We further investigate the underlying molecular mechanisms by focusing on the following two questions: 1) whether autophagy mediates BACE1 degradation in AD brains and is regulated by p38alpha-MAPK activation; 2) whether p38alpha-MAPK directly phosphorylates BACE1 or/and BACE1-sorting adaptor proteins (i.e. GGA1/3) and subsequently modulates their function and degradation. These studies should contribute to a better understanding of AD pathogenesis and identify new molecular targets for AD therapy.

• DFG Programme: Research Grants