Targeting nascent soluble Aβ42 for potential Alzheimer drug development

摘要

y-secretase is an essential enzyme for generation of amyloid P protein (A (3), a central component of neuritic plaques in Alzheimer's Disease (AD) brain. Identification of potent y-secretase inhibitors (GSIs) and y-secretase modulators (GSMs) that specifically inhibit production of AP42, an infamous molecule thought to be responsible for AD pathogenesis, has always been major interest to AD drug development. While a few of inhibitors and modulators have reached clinical trials, most screenings have only focused on in vitro potency test and specificity test. In this issue Mitani and colleagues reported the effect of GSM-2, a second generation GSM on A(342 and cognitive function in vivo using an AD model mice in an article titled 'Amelioration of cognitive deficits in plaque-bearing Alzheimer's disease model mice through selective reduction of nascent soluble A(342 without affecting other Ap pools' (Mitani et al. 2013). They discovered that GSM-2 lowered nascent A (342 level in vivo and improved memory deficits in both young and old age groups, indicating that GSM-2" may delay AD progression regardless of existing A[3 plaque load, and this is Likely due to reduction of newly synthesized soluble AP42 (Fig. 1).