02308nas a2200241   4500008004100000245013500041210007000176260001600246300000700262490000600269520143300275100001601708700002501724700001701749700002601766700002301792700001801815700002001833700001601853700002401869700001901893856015401912       2012                        ENG d00aTransient pharmacologic lowering of Aß production prior to deposition results in sustained reduction of amyloid plaque pathology.0 aTransient pharmacologic lowering of Aß production prior to depos  c2012 Aug 14  a390 v73 aABSTRACT: BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia among the elderly. Disease modifying therapies targeting Abeta that are in development have been proposed to be more effective if treatment was initiated prior to significant accumulation of Abeta in the brain, but optimal timing of treatment initiation has not been clearly established in the clinic. We compared the efficacy of transient pharmacologic reduction of brain Abeta with a gamma-secretase inhibitor (GSI ) for 1--3 months (M) treatment windows in APP Tg2576 mice and subsequent aging of the mice to either 15M or 18M. RESULTS: These data show that reducing Abeta production in a 2-3M windows both initiated and discontinued before detectable Abeta deposition has the most significant impact on Abeta loads up to 11M after treatment discontinuation. In contrast, initiation of treatment for 3M windows from 7-10M or 12-15M shows progressively decreasing efficacy. CONCLUSIONS: These data have major implications for clinical testing of therapeutics aimed at lowering Abeta production, indicating that; i) these therapies may have little efficacy unless tested as prophylactics or in the earliest preclinical stage of AD where there is no or minimal Abeta accumulation and ii) lowering Abeta production transiently during a critical pre-deposition window potentially provides long-lasting efficacy after discontinuation of the treatment.1 aDas, Pritam1 aVerbeeck, Christophe1 aMinter, Lisa1 aChakrabarty, Paramita1 aFelsenstein, Kevin1 aKukar, Thomas1 aMaharvi, Ghulam1 aFauq, Abdul1 aOsborne, Barbara, A1 aGolde, Todd, E  uhttps://www.umass.edu/veterinary-animal-sciences/research-faculty/publications/transient-pharmacologic-lowering-of-ass-production-prior-to-deposition