Targeting beta or gamma-Secretase, 2010 and 2011 patents summary 

Alzheimer’s disease is pathologically characterized by the deposition of amyloid in extracellular plaques and intracellular neurofibrillary tangles in the brain. These plaques mainly comprise aggregates of β-amyloid peptides (Aβ peptides) formed from Amyloid Precursor Protein (APP) by a series of proteolytic cleavage steps involving the enzymes β- and γ-secretase.

β-Secretase (also called BACE-1 for β-site APP-cleaving enzyme) was identified as a type 1 transmembrane protein containing aspartyl protease activity and primilarly cleaves APP to yield a secreted fragment of APP (sAPPβ) and a C-terminal fragment of APP (CTFβ).

CTFβis then cleaved by γ-secretase within the membrane to yield a smaller C-terminal fragment (CTFγ) and Aβfragments of different chain length (Ab38, Ab40, Ab42). γ-Secretase is a transmembrane protein complex that includes Nicastrin, APH-1, PEN-2, and either Presenilin-1 (PS-1) or Presenilin-2 (PS-2).

An alternate cleavage by α-secretase cuts within the Aβ domain, on the contrary prevents Aβgeneration.

The potential opportunities for therapeutic interventions are then:

• Inhibitors of APP production

• Activators of α-Secretase

• Inhibitors of β- and γ-Secretase

• Aβ production Modulators

Table 1. Current Secretase inhibitors in 2010’s patents*

*Source WIPO.