Modulation of gamma-secretase for the treatment of Alzheimer's disease

Abstract

The Amyloid Hypothesis states that the cascade of events associated with Alzheimer's disease (AD)-formation of amyloid plaques, neurofibrillary tangles, synaptic loss, neurodegeneration, and cognitive decline-are triggered by Aβ peptide dysregulation (Kakuda et al., 2006, Sato et al., 2003, Qi-Takahara et al., 2005). Since γ-secretase is critical for Aβ production, many in the biopharmaceutical community focused on γ-secretase as a target for therapeutic approaches for Alzheimer's disease. However, pharmacological approaches to control γ-secretase activity are challenging because the enzyme has multiple, physiologically critical protein substrates. To lower amyloidogenic Aβ peptides without affecting other γ-secretase substrates, the epsilon (ε) cleavage that is essential for the activity of many substrates must be preserved. Small molecule modulators of γ-secretase activity have been discovered that spare the ε cleavage of APP and other substrates while decreasing the production of Aβ(42). Multiple chemical classes of γ-secretase modulators have been identified which differ in the pattern of Aβ peptides produced. Ideally, modulators will allow the ε cleavage of all substrates while shifting APP cleavage from Aβ(42) and other highly amyloidogenic Aβ peptides to shorter and less neurotoxic forms of the peptides without altering the total Aβ pool. Here, we compare chemically distinct modulators for effects on APP processing and in vivo activity.

Figure 1

Multiple GSI and GSMs were examined in for their ability to inhibit NOTCH cleavage using the SUP-T1 cellular assay.

Figure 2

Representative NSAID-inspired GSMs. Compounds 1–6 are aryl acetic acids [–26], compounds 7 and 8 are piperidine acetic acids [27, 28] and compound 9 is a cyclohexane acetic acid [29].

Figure 3

Representative aryl imidazole inspired GSMs [–33]. Compounds 16–18 are the most unique because the aryl imidazole has been replaced by a bioisostere [–36].

Figure 4

Two examples of Satori GSMs.

Figure 5

Structures of SPI-1802 and SPI-1810 [20, 37].

Figure 6

MALDI-TOF analysis of Aβ peptides from conditioned media of APP-overexpressing CHO cells treated with GSMs. The immunoprecipitated Aβ peptides were subjected to MALDI-TOF analysis to visualize individual Aβ fragments. Using a combination of two Aβ antibodies, 6E10, and 4G8 allows precipitation of full length and N- and C-terminal truncated Aβ peptides.

Figure 7

Diagram highlighting the differences between inhibitors and modulators.