Nature Reviews Neurology | 2019
Stroke trial drug is effective in Alzheimer disease mouse model
Abstract
Nature reviews | Neurology Original article Lazic, D. et al. 3K3Aactivated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice. J. Exp. Med. https://doi.org/10.1084/jem. 20181035 (2019) this protein has already successfully completed a phase II clinical trial a drug that has been successful in a phase ii trial in patients with stroke prevents development of amyloid-β (aβ) pathology in a mouse model of alzheimer disease (aD), according to a recent study. the work identifies a new candidate drug for testing in early aD in humans. the drug — called 3K3a-activated protein C (aPC) — is a recombinant variant of endogenous aPC, a protease with anticoagulant, cytoprotective, vasculoprotective and anti-inflammatory properties. 3K3a-aPC has been engineered to retain the protective effects of aPC but minimize the associated risk of bleeding. Previous work has demonstrated that 3K3a-aPC protects neurons in animal models of stroke, traumatic brain injury, amyotrophic lateral sclerosis and multiple sclerosis. a phase iia trial has shown that the drug is safe, well tolerated and beneficial in patients with ischaemic stroke. “we thought 3K3a-aPC would be good to try in aD mice for direct protection of neurons from aβ toxicity, improving brain circulation and blood–brain barrier integrity, and reducing inflammation,” explains Berislav Zlokovic, lead author of the new study. to test their hypothesis, Zlokovic and colleagues treated 5XFaD mice, which express five mutations in the genes that encode amyloid precursor protein and presenilin 1, with 3K3a-aPC for 4 months. the mice were treated before the peak of aβ accumulation to investigate whether disease onset could be delayed. as the researchers hoped, treatment improved blood–brain barrier integrity and the treated mice exhibited behavioural improvements, but unexpected effects also occurred. “to our surprise, we also found greatly reduced aβ pathology and reductions in generation of aβ peptides, mediated via blockade of the NF-κB–BaCe1 pathway,” says Zlokovic. this pathway leads to production of aβ, which aggregates in the brain in aD. the findings indicate that 3K3a-aPC provides an opportunity to use a single drug to prevent aβ production in addition to providing neuronal and vascular protection and mitigating inflammation. “what is particularly attractive with 3K3a-aPC is the fact that this protein has already successfully completed a phase ii clinical trial and has shown clear target engagement in the living human brain,” explains Zlokovic. “we are now considering a proof-of-concept study in patients with early aD to show target engagement by monitoring cerebrospinal fluid and imaging biomarkers and with cognitive tests.” Ian Fyfe a l Z H e i M e r D i S e a S e