Neurology Central

Alzheimer’s disease may be prevented by experimental stroke drug

Researchers have discovered that 3K3A-APC, which is currently in development for treatment of ischemic stroke, may also prevent Alzheimer’s disease (AD).

Berislav V Zlokovic from the University of Southern California (CA, USA) and a multidisciplinary team have reported that 3K3A-APC inhibits BACE1 amyloidogenic pathways in a mouse model of AD. The results were published in the Journal of Experimental Medicine.

3K3A-APC reduces inflammation and protects both neurons and the cells that line the walls of blood vessels from degeneration and death. The drug is currently in development as a neuroprotectant for the treatment of ischemic stroke and has been shown to be safe, well tolerated and has the potential to reduce intracerebral bleeding in humans.

“Because of its neuroprotective, vasculoprotective, and anti-inflammatory activities in multiple models of neurological disorders, we investigated whether 3K3A-APC can also protect the brain from the toxic effects of amyloid-β toxin in a mouse model of AD,” explained Zlokovic.

The research team investigated the effects of 3K3A-APC in mouse models of AD expressing five autosomal dominant AD mutations in neurons, including Swedish, London, and Florida APP mutations and PSEN1 M146L and L286V mutations. The team found 3K3A-APC prevented the development of amyloid deposits in neurons, which slowed down the generation of amyloid-β in the mice administered with the drug.

“Our present data support the idea that 3K3A-APC holds potential as an effective anti-amyloid-β therapy for early-stage AD in humans,” commented Zlokovic.

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Zlokovic and colleagues also found that 3K3A-APC significantly reduced brain cortical mRNA and protein levels of BACE1, decreased approximately 50% of BACE1 cortical activity and decreased the levels of sAPPβ in the cerebrospinal fluid. The research team believe that these data together transcriptionally inhibit amyloidogenic BACE1 pathway.

Presently, BACE1 inhibition fails to stop cognitive decline in people with mild-to-moderate AD, suggesting that treating AD at the symptomatic stage may be too late. Therefore, based on animal model findings, it has been indicated that treatment with BACE1 inhibitors in individuals with early-stage AD and preventative trails before symptom onset could have a better outcome.

Commenting on the recent finding, Sara Imarisio, Head of Research at Alzheimer’s Research UK (Cambridge, UK) cautioned that: “…this is an early stage research study using a drug that is not yet licensed for use in people who have had a stroke.”

“As with any research in mice we must be careful how we analyse the results and much more work is required before a drug like this could be to be repurposed for use in people with Alzheimer’s or any other neurodegenerative disease.”

Looking forward the team suggest the neuroprotective, vasculoprotective, and anti-inflammatory effects of 3K3A-APC should be tested in late-stage APP mice models where other BACE1 inhibitors were ineffective.

Sources: Lazic D, Sagare AP, Nikolakopoulou AM et al. 3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice. J. Exp. Med. doi:10.1084/jem.20181035 (2019) (Epub ahead of print);;