Biotech Values

[biotech jim]

Not all gamma secretase inhibitors are created equal, as the enzyme is actually a multiprotein complex. Inhibiting Notch is a significant mechanistic side effect of at least some gamma secretase inhibitors.

There is also an activating protein for gamma secretase, see the following abstract:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936959/

Accumulation of neurotoxic ßamyloid (Aß) is a major hallmark of Alzheimer's disease (AD)1. Formation of Aß is catalyzed by ?secretase, a protease with numerous substrates2,3. Little is known about the molecular mechanisms that confer substrate specificity on this potentially promiscuous enzyme. Knowledge of the mechanisms underlying its selectivity is critical for the development of clinically effective ?-secretase inhibitors that can reduce Aß formation without impairing cleavage of other ?-secretase substrates, especially Notch, which is essential for normal biological functions3,4. Here we report the discovery of a novel ?-secretase activating protein (gSAP), which dramatically and selectively increases Aß production through a mechanism involving its interactions with both ?secretase and its substrate, the amyloid precursor protein C-terminal fragment (APP-CTF). gSAP does not interact with Notch nor does it affect its cleavage. Recombinant gSAP stimulates Aß production in vitro. Reducing gSAP levels in cell lines decreases Aß levels. Knockdown of gSAP in a mouse model of Alzheimers disease reduces levels of Aß and plaque development. gSAP represents a new type of ?-secretase regulator that directs enzyme specificity by interacting with a specific substrate. We demonstrate that imatinib, an anti-cancer drug previously found to inhibit Aß formation without affecting Notch cleavage5, achieves its Aß-lowering effect by preventing gSAP interaction with the ?-secretase substrate, APP-CTF. Thus, gSAP can serve as an Aß-lowering therapeutic target without affecting other key functions of ?-secretase.

The above abstract is from a NYC start-up named Intracellular Therapeutics.