Nothing to do with beta amyloid!

▎Editor of WuXi AppTec's content team Today, Nature Aging, a sub-Journal of Nature, published an important paper on Alzheimer's disease
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Researchers focused on Alzheimer's disease's greatest risk genes, ascertained its mechanism of action in mice, and are expected to bring new treatment methods
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It is worth mentioning that this potential therapy has nothing to do with beta amyloid in popular theory, and it can be said that it has expanded a whole new way! It is well known that the APOE4 allele is the largest genetic risk factor for Alzheimer's disease
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Compared with low-risk people carrying two APOE3 alleles, if ordinary people carry one APOE4 gene, the risk of Alzheimer's disease can be increased by 4 times
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If you carry two APOE4 genes, the risk will increase by 15 times! What is the ability of APOE4 gene and how can it have a huge impact on Alzheimer's disease? In April last year, the team of Professor Berislav Zlokovic of the University of Southern California published an article in the journal Nature, revealing the mystery behind it: It turns out that this gene can cause degenerative changes in the capillary pericytes of the brain and accelerate the blood-brain barrier.
Destroy
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▲A study in April last year laid the foundation for this article (picture source: screenshot of the official website of Nature), which makes it easier for toxic substances in the blood to enter the brain, damage brain cells, and affect cognitive function
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And no matter whether the patient has beta amyloid or not, there will be memory problems
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Based on these findings, Professor Zlokovic’s team has made persistent efforts to further explore the mechanism by which APOE4 gene destroys pericytes in the study published today.

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Researchers have found that with the destruction of pericytes, the level of "cyclophilin A" in the blood vessels of Alzheimer's disease patients will increase, and it is precisely a pro-inflammatory protein
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Considering the recent emergence of the "inflammation hypothesis" of Alzheimer's disease, cyclophilin A has also received special attention from scientists
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▲ Cyclophilin A (red in the upper image) activated in the brain pericytes will activate MMP9 (red in the lower image) and affect the capillaries (blue) (picture source: reference [2]; Credit: Angeliki Nikolakopoulou, PhD ) In a mouse model carrying APOE4, the researchers pointed out that cyclophilin A can activate an enzyme called "matrix metalloproteinase A 9" (abbreviated as MMP9)
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This enzyme destroys the blood vessels in the blood-brain barrier, thereby destroying the blood-brain barrier
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Interestingly, in mice carrying APOE3, the researchers did not observe this phenomenon
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This can also explain why APOE4 is the genetic risk factor for Alzheimer's disease
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Considering that cyclophilin A plays a role in regulating the integrity of blood vessels in pericytes, the authors of this paper naturally wondered whether if cyclophilin A can be inhibited, could it be possible to avoid activation of MMP9, thereby protecting the blood-brain barrier.
Completeness? ▲ Cyclophilin inhibitors can improve the condition of APOE4 mice (picture source: Reference [1]) In order to test this idea, scientists used a cyclophilin A inhibitor in mice carrying APOE4, and the results Just as they expected! Under the action of inhibitors, even if they carry the APOE4 gene, the integrity of the blood-brain barrier in mice can be improved
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More importantly, this inhibitor can also prevent the loss of neurons and prevent behavioral problems in mice! Taken together, this study shows that drugs targeting the cyclophilin A-MMP9 pathway are expected to alleviate the vascular abnormalities and neurodegenerative symptoms caused by the APOE4 gene
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If this discovery can be repeated in the human body, the impact will be huge
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"So far, patients with advanced Alzheimer's disease have almost no (treatment) hope.
This is a very difficult thing for patients and their loved ones," commented Professor Zlokovic, the research leader.
" we may focus on interventions to repair the blood brain barrier and on the strength of blood vessels, regardless of the amyloid pathology
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this is expected to slow in late in Alzheimer's disease, and even the termination of the recession neurodegeneration and cognitive abilities
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can We are very excited to study this potential therapy
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"▲Professor Berislav Zlokovic, the corresponding author of this study (Image source: University of Southern California; Credit: Richard Carrasco) It is worth mentioning that the cyclophilin A inhibitor used in this study The agent is called Debio-025 (alisporivir), which itself is a hepatitis C therapy
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In the future, people will also evaluate its new potential in the treatment of Alzheimer's disease
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Title of this article: 123RF References: [1] Montagne, A.
, Nikolakopoulou, AM, Huuskonen, MT et al.
APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer's mice via cyclophilin A independently of amyloid-β.
Nat Aging 1, 506–520 (2021).
https://doi.
org/10.
1038/s43587-021-00073-z[2] USC study reveals potential new treatment target for Alzheimer's disease, Retrieved June 14, 2021, from https:/ /