β-Secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice

Alzheimer disease is intimately linked to an excess amount of amyloid-beta (A beta) in the brain. Thus, therapeutic inhibition of A beta production is an attractive clinical approach to treat this disease. Here we provide the first direct experimental evidence that the treatment of Tg2576 transgenic mice with an inhibitor of beta-secretase, GRL-8234, rescues the age-related cognitive decline. We demonstrated that the injected GRL-8234 effectively enters the brain and rapidly decreases soluble A beta in the brain of Tg2576 mice. The rescue of cognition, which was observed only after long-term inhibitor treatment ranging from 5 to 7.5 mo, was associated with a decrease of brain amyloid-beta plaque load. We also found no accumulation of amyloid-beta precursor protein after several months of inhibitor treatment. These observations substantiate the idea that A beta accumulation plays a major role in the cognitive decline of Tg2576 mice and support the concept of A beta reduction therapy as a treatment of AD.-Chang, W.-P., Huang, X., Downs, D., Cirrito, J. R., Koelsch, G., Holtzman, D. M. Ghosh, A. K., Tang, J. beta-Secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice. FASEB J. 25, 775-784 (2011). www.fasebj.org