Inhibiting stalled gamma secretase complexes for Alzheimer's therapeutics

Overview

Alzheimer's disease (AD) is marked by the accumulation of abnormal proteins, particularly amyloid-beta (Aβ), in the brain. This research targets stalled gamma-secretase enzyme-substrate complexes to reduce the production of pathogenic Aβ, thereby addressing synaptic degeneration and neuroinflammation in AD. By inhibiting these complexes, the generation of long amyloid-beta peptides, which are a core component of AD senile plaques, can be reduced, potentially offering a novel therapeutic pathway.

Technical specifications

Gamma-secretase is a protease complex responsible for the cleavage of amyloid precursor protein (APP), a key step in Aβ production. Previous attempts at inhibiting gamma-secretase were unsuccessful. This research identifies a novel dysfunction in gamma-secretase protease stability, targeting it with new protease inhibitors. The focus is on developing inhibitors with high specificity and adequate pharmacokinetics for use in animal studies. Validation involves testing these inhibitors in AD amyloidosis mouse models to assess reductions in Aβ load and improvements in neuronal function and behavior.

Technology readiness level

The current stage of development is at Technology Readiness Level 3. Proof of concept has been established in cell models and AD model mice through genetic and biochemical assays. Further validation will involve developing specific protease inhibitors and conducting comprehensive tests in mouse models over a two-year study period.