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Mai Nakamura

Class 2013
Education BS, Duke University
Email mnakam14@jhmi.edu
Mentor

Dr. Shan Sockanathan

Research Interests

Alzheimer’s Disease (AD) pathogenesis is characterized by the overproduction of amyloid-β (Aβ) peptides. These Aβ peptides are formed by sequential cleavage of Amyloid Precursor Protein (APP) by the proteases β- and γ-secretase. Additionally, recent work has shown that APP can be cleaved by the α-secretase ADAM10 in a pathway that confers neuroprotection by production of the secreted fragment sAPPα. In AD, however, the homeostasis between α- and β-cleavage is perturbed, resulting in accumulation of Aβ peptides through increased β-cleavage. While pathways regulating the production of Aβ have been extensively studied, very few have focused on the biogenesis of neuroprotective sAPPα. Elucidating the molecular mechanisms regulating α-cleavage could therefore significantly advance our knowledge of the pathogenesis underlying AD.

In neurodevelopment, the glycophosphatidylinositol- (GPI-) anchored protein RECK antagonizes the metalloprotease ADAM10, which in turn modulates Notch signaling. Previously, our lab has found that the six-transmembrane protein Glycerophosphodiester Phosphodiesterase 2 (GDE2), and its close paralog Glycerophosphodiester Phosphodiesterase 3 (GDE3), regulates this process by cleaving the GPI anchor of RECK, thus inactivating RECK and promoting ADAM10 enzymatic activity.

We have recently found evidence of neurodegenerative pathology in mice lacking GDE2 or GDE3 (Gde2-/-, Gde3-/-). These results point to the exciting possibility that the GDE/RECK/ADAM10 signaling axis may not only play a role in neurodevelopment but may also be involved in APP processing and therefore neurodegeneration. My thesis project seeks to further characterize the neurodegenerative effects caused by loss of Gde2 and Gde3 and to investigate whether RECK disinhibition of ADAM10 by the GDE proteins is neuroprotective in AD, in part through modulation of α- and β-cleavage products.