γ-Secretase Inhibitors for Alzheimer’s Disease

摘要: The amyloid hypothesis, which states that β-amyloid (Aβ) aggregates cause the onset and progression of Alzheimer’s disease (AD), is a leading proposal to explain AD aetiology. Based on this compounds inhibit γ-secretase, one enzymes responsible for forming Aβ, are potential therapeutics AD. Preclinical studies clearly establish γ-secretase inhibitors can reduce brain Aβ in rodent models. initial investigation effects inhibitor Aβ-induced cognitive deficits transgenic mice showed modest reductions (15–30%) sufficient reverse Tg2576 mice. Extending these other models with will be important. Unfortunately, also abnormalities gastrointestinal tract, thymus spleen rodents. These changes likely result from inhibition Notch cleavage, transmembrane receptor involved regulating cell-fate decisions. Two recent rodents suggest reduction using partially separated inhibition. Given uncertain target mechanism-based toxicity, biomarkers efficacy toxicity would helpful clinical trials. first report trials was recently published. In study, LY-450139 reduced plasma but not cerebrospinal fluid Aβ. Taken together, results date have address large unmet medical need if technical challenges overcome.