The study “3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice” was published in The Journal of Experimental Medicine. 

“Our present data support the idea that 3K3A-APC holds potential as an effective anti-amyloid-β [beta] therapy for early stage Alzheimer’s disease in humans,” Berislav V. Zlokovic, lead author of the study, said in a press release. Zlokovic is director of the Zilkha Neurogenetic Institute at the Keck School of Medicine, University of Southern California.

3K3A-APC, a genetically modified form of a natural human blood protein called activated protein C (APC), was shown to have beneficial therapeutic effects in mouse models of stroke, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS).

The therapy reduces inflammation and protects neurons from a programmed cell death (called apoptosis). It also helps maintain the integrity of cells that line the walls of blood vessels after an injury and those of the blood brain barrier, a highly selective membrane that shields the central nervous system from the general blood circulation.

Researchers at the University of Southern California hypothesized that because 3K3A-APC has multiple benefits in several models of neurological disorders, it also could protect the brain from toxic effects of amyloid-beta deposition, a hallmark of Alzheimer’s disease.

“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 Alzheimer’s disease,” Zlokovic said.

Researchers treated a mouse model of Alzheimer’s disease with daily injections of 3K3A-APC or an innocuous substance (control group), delivered intraperitoneally (directly into the abdomen) for four months.

Treatment with 3K3A-APC led to a significant reduction of total brain amyloid-beta load, by 40 to 50%, when compared to controls, specifically in two regions of the brain: the hippocampus and cortex.

The effects of 3K3A-APC in the hippocampus, linked to memory and spatial navigation, were in agreement with the therapy’s functional benefits; the treatment prevented memory loss in these animals. Additionally, 3K3A-APC helped maintain a normal cerebral blood flow and suppressed neuroinflammation, commonly seen in Alzheimer’s disease.

3K3A-APC, researchers found, works by preventing the production of the BACE1 enzyme, a key factor required for the synthesis of amyloid-beta. BACE1 is one of the prime targets of Alzheimer’s therapies seeking to reduce the levels of amyloid-beta in the brains of Alzheimer’s patients.

Increasing evidence suggests that the optimal timing for BACE1 inhibitors to be effective is during the early stages of the disease, before amyloid-beta accumulation occurs, leading to permanent brain damage.

“Since 3K3A-APC is safe and well tolerated in humans including stroke patients, the present data support that 3K3A-APC holds potential as an effective anti-Aβ [amyloid-beta] therapy for early-stage AD [Alzheimer’s disease] in humans,” researchers wrote.

This is not the first time a stroke therapy has shown potential to treat Alzheimer’s disease. In October 2018, fasudil, a chemical inhibitor used to treat strokes, also was suggested as a potential therapy for preventing early nerve cell impairment and beta-amyloids’ damaging effects.