Gamma-secretase is a key enzyme in generation of amyloid beta (Aβ) and accumulation of Aβ is a pathological hallmark of Alzheimer's disease (AD). Therefore, inhibition of γ-secretase is a potential therapeutic target. Gamma-secretase has many (>40) substrates in addition to Aβ precursor protein. Since some substrates, such as Notch, is a critical in physiological system, presumably, substrate selectivity is critical to gain desired safety profile. First generation γ-secretase inhibitors (GSIs) have only limited (if there is any) substrate selectivity, and also induced paradoxical increase of Aβ after transient reduction (Aβ-rebound) in pre-clinical species and human. We investigated mechanism of Aβ-rebound using GSI and γ -secretase modulators (GSMs) which shift cleavage site and maintain cleavage of substrates. We found that an accumulation of γ-secretase substrates is one of causes of GSI-mediated Aβ-rebound. In combination of substrate selectivity, GSMs may be more useful Aβ-lowering approach for treatment AD.
　　Acute and transient increase of Aβ is seen after traumatic brain injury in pre-clinical species and human. We hypothesized overproduction of Aβ is one of causes of neurodegeneration and tested impact of Aβ-lowering approach using GSI. Treatment with a GSI significantly reduced neurodegeneration and improved dysfunction. GSI and other Aβ-lowering agents may be useful for treatment of traumatic brain injury.