Rho-associated protein kinase 2–Beta-secretase 1 protein-protein interface (ROCK2–BACE1 PPI)

The Rho-associated protein kinase 2 (ROCK2)–Beta-secretase 1 (BACE1) protein-protein interface is a therapeutic target for Alzheimer's disease (Herskowitz et al., 2013, J Neurosci). ROCK2 is a serine/threonine kinase that regulates the stability and activity of BACE1, the rate-limiting enzyme in the production of amyloid-beta (Aβ) peptides (Deyts et al., 2019, J Biol Chem). By interacting with BACE1, ROCK2 promotes the amyloidogenic processing of amyloid precursor protein (APP) (UniProt O75116). Disrupting this specific protein-protein interaction (PPI) or inhibiting ROCK2 activity has been shown to reduce BACE1 levels and subsequent Aβ accumulation in preclinical models (PubMed: 23946399). This approach is considered a potential strategy to mitigate the toxicity associated with global BACE1 inhibition, which has faced challenges in clinical trials due to the processing of other physiological substrates (Science Translational Medicine, 2013). ROCK2 is highly expressed in the brain, making it a tissue-specific modulator of BACE1 that could offer a wider therapeutic window than traditional secretase inhibitors (Herskowitz et al., 2013).

Other names

ROCK2-BACE1 complexROCK2-BACE1 interactionRho-associated protein kinase 2–Beta-site amyloid precursor protein cleaving enzyme 1 interface

Disruption of the protein-protein interaction or inhibition of ROCK2-mediated stabilization of BACE1 to reduce amyloid-beta production.