Role of gamma-secretase in cellular cholesterol metabolism

• Applicant: Naoto Oikawa, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 348207315

Cholesterol plays critical roles in brain function, including intraneuronal vesicular trafficking and synaptic activity. Accordingly, impaired cholesterol metabolism is associated with several brain diseases. Cholesterol dysregulation is also considered to contribute to the pathogenesis of Alzheimer disease (AD). Intriguingly, abnormal cellular cholesterol metabolism is also found in familial AD cases caused by presenilin mutations. These mutations appear to cause AD development through dysfunction of gamma-secretase, in which the presenilin proteins act as a catalytic subunit. However, the mechanism how gamma-secretase dysfunction leads to abnormal cellular cholesterol metabolism is still under elucidation. Preliminary experiments demonstrate that gamma-secretase dysfunction causes impairment of lipoprotein/receptor endocytosis and up-regulation of cellular cholesterol synthesis. The central aim of this project is to identify and characterize the molecular mechanisms underlying abnormal neuronal cholesterol metabolism upon AD-related gamma-secretase dysfunction.

• DFG Programme: Research Grants