Potential new treatment target for Alzheimer's disease [Debio-025, a Cyclophilin A suppressor]

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Potential new treatment target for Alzheimer's disease [Debio-025, a Cyclophilin A suppressor]

Post by BrianR »

[There are a few previous APOE4 forum posts discussing Cyclophilin A's actions in the brain.]

Science Daily explainer: https://www.sciencedaily.com/releases/2 ... 131220.htm
Researchers then tried treating APOE4 mice with an inhibitor known to suppress Cyclophilin A. The inhibitor not only improved integrity in the blood-brain barrier in APOE4 mice, but also prevented development of further neuron loss and behavioral deficits. Researchers observed that the APOE4 mice treated with the inhibitor did not exhibit behavioral deficits during daily activities. This suggests that treatment targeting this pathway might have the potential to also slow down the progression of vascular and neurodegenerative disorders in people with Alzheimer's disease who have the APOE4 gene.

"So far there has been little hope for those in the late stage of the disease, which is very hard on patients and their loved ones," said Zlokovic. "We are excited to further study the potential that interventions focused on blood-brain barrier repair and blood vessel strength, independent of amyloid pathology, could have on slowing down or stopping neurodegeneration and cognitive decline in advanced Alzheimer's disease."

The inhibitor used in this study to suppress the Cyclophilin A, Debio-025, has been used in humans to treat hepatitis C, suggesting this could be a potential treatment for cognitive impairment in APOE4 carriers that show Cyclophilin A-MMP9 pathway activity in early or late disease stages.
From open access paper:
APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β
Axel Montagne, Angeliki M. Nikolakopoulou, Mikko T. Huuskonen, Abhay P. Sagare, Erica J. Lawson, Divna Lazic, Sanket V. Rege, Alexandra Grond, Edward Zuniga, Samuel R. Barnes, Jacob Prince, Meghana Sagare, Ching-Ju Hsu, Mary J. LaDu, Russell E. Jacobs & Berislav V. Zlokovic
Nature Aging volume 1, pages 506–520 (2021)
DOI: 10.1038/s43587-021-00073-z
Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer’s disease (AD), leads to vascular dysfunction, amyloid-β pathology, neurodegeneration and dementia. How these different pathologies contribute to advanced-stage AD remains unclear. Using aged APOE knock-in mice crossed with 5xFAD mice, we show that, compared to APOE3, APOE4 accelerates blood–brain barrier (BBB) breakdown, loss of cerebral blood flow, neuronal loss and behavioral deficits independently of amyloid-β. BBB breakdown was associated with activation of the cyclophilin A-matrix metalloproteinase-9 BBB-degrading pathway in pericytes. Suppression of this pathway improved BBB integrity and prevented further neuronal loss and behavioral deficits in APOE4;5FAD mice while having no effect on amyloid-β pathology. Thus, APOE4 accelerates advanced-stage BBB breakdown and neurodegeneration in Alzheimer’s mice via the cyclophilin A pathway in pericytes independently of amyloid-β, which has implication for the pathogenesis and treatment of vascular and neurodegenerative disorder in AD.
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Re: Potential new treatment target for Alzheimer's disease [Debio-025, a Cyclophilin A suppressor]

Post by Fiver »

Hi Brian, I saw this yesterday as well. This is a large paper, very thorough, with big effect sizes. Debio-025 really did seem to fix BBB and blood flow problems AND prevent the worsening of cognitive problems in these mice carrying human apoe4 genes. Sadly it did not restore lost cognition but I'm not sure the experiment was designed to look at that (it probably would take much longer). Anyway, this was exiting to me. Much more exciting than taking another ride on the ole' amyloid train to nowhere.

I hope they get to clinical trials for AD soon. There are ongoing trials of this drug against viruses already - maybe there is data there that would give them a jump start. I wish the research community would move on things like this with more urgency - can't fault the researchers but the drug discovery landscape can obviously be sped up when necessary. This would be a good one to "warp speed" ahead.
Concerned, but hopeful. Introverted, but will talk about science.
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Re: Potential new treatment target for Alzheimer's disease [Debio-025, a Cyclophilin A suppressor]

Post by xactly »

Rhonda Patrick did an interview with Axel Montagne about blood-brain barrier repair in Episode 79 of Found My Fitness, posted April 27, 2023. I learned from a recent MRI that I have FLAIR hyperintensities that are probably caused by small vessel ischemic disease. In this episode, Montagne describes how epithelial activation through proteins like MMP9 and cyclophilin A degrades tight junctions in the BBB, leading to pericyte loss and neuron death. (APOE4 carriers have four times more MMP9 and cyclophilin A than non-carriers.) Montagne talks about research his lab and others are conducting to identify targets to preserve barrier integrity and reduce epicyte loss. Reducing fibrinogen in plasma improved outcomes in a mouse model; diet and exercise are good lifestyle interventions for reducing fibrinogen.
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