{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T23:55:17Z","timestamp":1792194917574,"version":"4.4.0"},"reference-count":23,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2009,3,18]],"date-time":"2009-03-18T00:00:00Z","timestamp":1237334400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2009,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Accumulation of amyloid\u2010\u03b2 (A\u03b2) by overproduction or underclearance in the central nervous system (CNS) is hypothesized to be a necessary event in the pathogenesis of Alzheimer's disease. However, previously, there has not been a method to determine drug effects on A\u03b2 production or clearance in the human CNS. The objective of this study was to determine the effects of a \u03b3\u2010secretase inhibitor on the production of A\u03b2 in the human CNS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We utilized a recently developed method of stable\u2010isotope labeling combined with cerebrospinal fluid sampling to directly measure A\u03b2 production during treatment of a \u03b3\u2010secretase inhibitor, LY450139. We assessed whether this drug could decrease CNS A\u03b2 production in healthy men (age range, 21\u201350 years) at single oral doses of 100, 140, or 280mg (n = 5 per group).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>LY450139 significantly decreased the production of CNS A\u03b2 in a dose\u2010dependent fashion, with inhibition of A\u03b2 generation of 47, 52, and 84% over a 12\u2010hour period with doses of 100, 140, and 280mg, respectively. There was no difference in A\u03b2 clearance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Stable isotope labeling of CNS proteins can be utilized to assess the effects of drugs on the production and clearance rates of proteins targeted as potential disease\u2010modifying treatments for Alzheimer's disease and other CNS disorders. Results from this approach can assist in making decisions about drug dosing and frequency in the design of larger and longer clinical trials for diseases such as Alzheimer's disease, and may accelerate effective drug validation. Ann Neurol 2009<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.21623","type":"journal-article","created":{"date-parts":[[2009,3,19]],"date-time":"2009-03-19T09:42:18Z","timestamp":1237455738000},"page":"48-54","source":"Crossref","is-referenced-by-count":270,"title":["A \u03b3\u2010secretase inhibitor decreases amyloid\u2010\u03b2 production in the central nervous system"],"prefix":"10.1002","volume":"66","author":[{"given":"Randall J.","family":"Bateman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric R.","family":"Siemers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwasi G.","family":"Mawuenyega","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guolin","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen 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