Scios Inc.

Eli Lilly and Company

Yu-Wang Liu

Barbara Cordell

Diana Hom Quon

Qiang Xu

Ziyang Zhong

Sheila P Little

Edward Marion Johnstone

Paul Andrew Hyslop

Frauke Schimmöller

Steven Wyatt Queener

Tinggui Yin

Frauke Schimmöoller

Frauke Schimm&ouml;ller

The present invention is based on the findings that BACE2, a homolog of &#x3b2;-secretase BACE, is able to stimulate processing of APP in a non-amyloidogenic pathway, thereby suppressing the level of A&#x3b2;. Accordingly, the present invention provides methods and means for the identification and use of modulators of this unique activity of BACE2 to suppress A&#x3b2; production. The compounds identified using the methods and means provided herein may be used as potential candidates for the treatment of Alzheimer's disease and other neurological diseases by reducing &#x3b2;-amyloid deposit formation.

Inhibition of A&#x3b2; production by &#x3b2;-secretase BACE2

The invention concerns a novel &#x3b2;-secretase, a method of partially purifying this novel &#x3b2;-secretase, and its use in assays to screen for potential drug candidates against Alzheimer's disease and other neurological diseases. The novel &#x3b2;-secretase has an estimated molecular weight of about 32-39 kDa or 22-26 kDa in HEK293 cell membrane extracts and human brain samples, respectively, as calculated from radiation inactivation analysis, and has a pH optimum at about pH 6.5-7.0.

&#x3b2;-secretase and modulation of &#x3b2;-secretase activity

The invention concerns a novel &#x3b2;-secretase, a method of partially purifying this novel &#x3b2;-secretase, and its use in assays to screen for potential drug candidates against Alzheimer's disease and other neurological diseases. The novel &#x3b2;-secretase has an estimated molecular weight of about 32&#x2013;39 kDa or 22&#x2013;26 kDa in HEK293 cell membrane extracts and human brain samples, respectively, as calculated from radiation inactivation analysis, and has a pH optimum at about pH 6.5&#x2013;7.0.

The present invention is based on the findings that BACE 2, a homolog of &bgr;-secretase BACE, is able to stimulate processing of APP in a non-amyloidogenic pathway, thereby suppressing the level of A&bgr;. Accordingly, the present invention provides methods and means for the identification and use of modulators of this unique activity of BACE 2 to suppress A&bgr; production. The compounds identified using the methods and means provided herein may be used as potential candidates for the treatment of Alzheimer's disease and other neurological diseases.

Modulation of A&bgr; levels by &bgr;-secretase BACE2

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Santa Clara, CA, United States of America

Yu-Wang Liu