Therapeutic Effects of a Novel Synthetic α-Secretase Provisionally Accepted

Sung Bin Kim¹ Bo-Ram Mun² Sung Yoon Kim¹ Muthukumar Elangovan¹ Euy Jun Park¹ Won-Seok Choi² Woo Jin Park^1*

• ¹School of Life Sciences, Gwangju Institute of Science and Technology, Republic of Korea
• ²School of Biological Sciences and Technology, Chonnam National University, Republic of Korea

Excessive accumulation of amyloid-β (Aβ) has been associated with the pathogenesis of Alzheimer's disease (AD). Clinical studies have further proven that elimination of Aβ can be a viable therapeutic option. In the current study, we conceptualized a fusion membrane protein, referred to as synthetic α-secretase (SAS), that can cleave amyloid precursor protein (APP) and Aβ specifically at the α-site. In mammalian cells, SAS indeed cleaved APP and Aβ at the α-site. Overexpression of SAS in the hippocampus was achieved by direct injection of recombinant adeno-associated virus serotype 9 (AAV9) that expresses SAS (AAV9-SAS) into the bilateral ventricles of mouse brains. SAS enhanced the non-amyloidogenic processing of APP, thus reducing the levels of soluble Aβ and plaques in the 5xFAD mice. In addition, SAS significantly attenuated the cognitive deficits in 5xFAD mice, as demonstrated by novel object recognition and Morris water maze tests. Unlike other Aβcleaving proteases, SAS has highly strict substrate specificity. We propose that SAS can be an efficient modality to eliminate excessive Aβ from diseased brains.