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Stroke Drug May Also Prevent Alzheimer’s

Summary: Researchers report a new drug being developed to treat stroke patients may also have neuroprotective properties against Alzheimer’s disease.

Source: Rockefeller University Press.

Researchers from the University of Southern California have discovered that a drug currently being developed to treat stroke patients could also prevent Alzheimer’s disease. The study, which will be published January 15 in the Journal of Experimental Medicine, shows that the genetically engineered protein 3K3A-APC protects the brains of mice with Alzheimer’s-like symptoms, reducing the buildup of toxic peptides and preventing memory loss.

3K3A-APC is a genetically modified version of a human blood protein called activated protein C, which reduces inflammation and protects both neurons and the cells that line the walls of blood vessels from death and degeneration. 3K3A-APC has beneficial effects in various mouse models of disease, including traumatic brain injury and multiple sclerosis, and is currently being developed to treat stroke in humans, where it has been shown to be safe, well tolerated, and capable of reducing intracerebral bleeding.

“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,” says Berislav V. Zlokovic, Director of the Zilkha Neurogenetic Institute at the Keck School of Medicine, University of Southern California.

brain slices

The new paper to be published in Journal of Experimental Medicine shows that 3K3A-APC (right) greatly reduces the amount of amyloid-β (green) that accumulates in the brains of mice that develop Alzheimer’s-like symptoms compared with no treatment (left).NeuroscienceNews.com image is credited to Lazic et al., 2019.

Toxic amyloid-β peptides accumulate in the brains of Alzheimer’s patients, leading to neurodegeneration and reduced blood flow within the brain. Zlokovic and colleagues found that 3K3A-APC significantly reduced the accumulation of amyloid-β in the brains of mice that usually produce large amounts of the toxic peptide. 3K3A-APC treatment prevented these mice from losing their memory and helped maintain normal cerebral blood flow. The drug also suppressed inflammation within the brain, another common feature of Alzheimer’s disease.

Zlokovic and colleagues found that 3K3A-APC protects the brain by preventing nerve cells from producing an enzyme called BACE1 that is required to produce amyloid-β. Several different inhibitors of BACE1 have been tested in clinical trials for Alzheimer’s disease, but the new study suggests that using 3K3A-APC to block the production of BACE1 could be an alternative approach, particularly at early stages of the disease when amyloid-β has yet to accumulate to levels capable of permanently damaging the brain.

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

About this neuroscience research article

Funding: Study funded by National Institutes of Health, University of Southern California.

Source: Ben Short – Rockefeller University Press
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to Lazic et al., 2019.
Original Research: Abstract for “3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice” by Divna Lazic, Abhay P. Sagare, Angeliki M. Nikolakopoulou, John H. Griffin, Robert Vassar, and Berislav V. Zlokovic in Journal of Experimental Medicine. Published January 2019.
doi:10.1084/jem.20181035

Cite This NeuroscienceNews.com Article
Rockefeller University Press”Stoke Drug May Also Prevent Alzheimer’s.” NeuroscienceNews. NeuroscienceNews, 15 January 2019.
<http://neurosciencenews.com/stroke-drug-alzheimers-10548/>.
Rockefeller University Press(2019, January 15). Stoke Drug May Also Prevent Alzheimer’s. NeuroscienceNews. Retrieved January 15, 2019 from http://neurosciencenews.com/stroke-drug-alzheimers-10548/
Rockefeller University Press”Stoke Drug May Also Prevent Alzheimer’s.” http://neurosciencenews.com/stroke-drug-alzheimers-10548/ (accessed January 15, 2019).

Abstract

3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice

3K3A-activated protein C (APC), a cell-signaling analogue of endogenous blood serine protease APC, exerts vasculoprotective, neuroprotective, and anti-inflammatory activities in rodent models of stroke, brain injury, and neurodegenerative disorders. 3K3A-APC is currently in development as a neuroprotectant in patients with ischemic stroke. Here, we report that 3K3A-APC inhibits BACE1 amyloidogenic pathway in a mouse model of Alzheimer’s disease (AD). We show that a 4-mo daily treatment of 3-mo-old 5XFAD mice with murine recombinant 3K3A-APC (100 µg/kg/d i.p.) prevents development of parenchymal and cerebrovascular amyloid-β (Aβ) deposits by 40–50%, which is mediated through NFκB–dependent transcriptional inhibition of BACE1, resulting in blockade of Aβ generation in neurons overexpressing human Aβ-precursor protein. Consistent with reduced Aβ deposition, 3K3A-APC normalized hippocampus-dependent behavioral deficits and cerebral blood flow responses, improved cerebrovascular integrity, and diminished neuroinflammatory responses. Our data suggest that 3K3A-APC holds potential as an effective anti-Aβ prevention therapy for early-stage AD.

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