Moderate Reduction of γ-Secretase Attenuates Amyloid Burden and Limits Mechanism-Based Liabilities

• DOI: 10.1523/jneurosci.2152-07.2007
• Publication Date: 2007-10-03T16:28:07Z
• Authors: Tong Li; Hongjin Wen; Cory Brayton; Fiona M. Laird; Guojun Ma; Shiwen Peng; Lisa Placanica; T. C. Wu; Barbara J. Crain; Donald L. Price; Charles G. Eberhart; Philip C. Wong
• Keywords: Amyloid (mycology); BACE1-AS; Gamma secretase

Although γ-secretase is recognized as a therapeutic target for Alzheimer's disease, side effects associated with strong inhibition of this aspartyl protease raised serious concerns regarding strategy. However, it not known whether moderate enzyme will allow dissociation beneficial in the CNS from mechanism-based toxicities periphery. We tested possibility by using series mice genetic reduction (levels ranging 25 to 64% control mice). Here, we document that even 30% can effectively ameliorate amyloid burden CNS. global below threshold level increased risk developing squamous cell carcinoma well abnormal proliferation granulocytes dosage-dependent manner. Importantly, demonstrate there exists critical reduces amyloidosis and limits tumorigenesis epithelia. Our findings suggest represents an attractive anti-amyloid therapy disease.