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Written by | A fish
Medin amyloid aggregates are present in almost all human vascular systems over the age of 50 and are the most prevalent amyloid
known to be present.
Medin is a 50-amino acid peptide formed by cleavage of the MFG-E8 protein
.
Although medin amyloid is so common in the elderly population, how it is produced and whether it contributes to the occurrence of the disease remains unclear
.
On November 16, 2022, Jonas J.
Neher's research team from the University of Tübingen in Germany published an article in Nature titled Medin co-aggregates with vascular amyloid-β in Alzheimer's disease In AD patients and model mouse brain blood vessels, medin co-localized with Aβ, knocking out medin can inhibit Aβ deposition, AD patients have higher levels of MFGE8 expression, and are associated with
cognitive decline.
Studies have found that medin aggregates increase in the cerebral arterioles in patients with vascular dementia or Alzheimer's disease (AD), so does elevated medin levels lead to a pathological phenotype of Alzheimer's disease? The researchers first stained the brain tissue of two AD mode mice (APPPS1 and APP23) for MFG-E8 and found that medin was colocalized
with amyloid angiopathy (CAA) β the brain.
Next, to examine the role of MFG-E8 and medin in β amyloid lesions, they used Mfge8 C2 knockout mice that were missing the C2 domain of MFG-E8, which contains medin
.
They found that the deletion of medin in AD mode mice significantly reduced plaque deposition that occurred in early pathology, and the CAA burden was reduced by about 85% in knockout mice compared to controls, indicating that MFG-E8 or medin promotes Aβ aggregation
in blood vessels.
To investigate the role of medin in human AD pathology, they examined the brain tissue of 16 AD deceased patients and found that medin was also colocalized
with Aβ 。 To further investigate the relationship between medin and CAA, they isolated cerebral blood vessels from the occipital cortex region and found that the protein levels of MFG-E8 in the cerebral blood vessels were 30-40 times higher than those in the total brain homogeneous sample of the same individual, in addition, compared to AD patients with no or low CAA, the protein levels of MFG-E8 were 2.
3 times higher in the blood vessels of patients with high CAA, and the protein levels of MFG-E8 were also positively correlated
with Aβ levels.
Therefore, elevated MFG-E8 levels are associated with
CAA in AD patients.
Next, to investigate the relationship between MFG-E8 and dementia, they analyzed MFGE8 gene expression levels in dorsal prefrontal cortex samples from 566 patients in the database and found that MFGE8 expression was significantly increased in AD patients, higher MFGE8 expression levels were significantly associated with cognitive decline, and did not depend on Aβ plaque load and tau pathology
.
In order to further investigate how medin promotes Aβ aggregation, they first used immunoelectron microscopy to analyze the subcellular localization of medin and MFG-E8 around Aβ plaques in mouse brain tissues, and found that amyloid fibers disappeared after knocking out medin, and further experimental results showed that Aβ can co-aggregate with medin, and medin and Aβ directly interact and promote its aggregation
.
Finally, they conducted in vivo experiments, which showed that medin can accelerate β amyloids in vivo, and exogenous medin aggregation can induce early maturation
of Aβ.
Overall, this study provides direct evidence for the interaction between Aβ and medin, proving that medin can co-aggregate with Aβ, and medin promotes Aβ deposition, looking forward to targeting medin as a new clinical strategy
for the treatment of AD in the future.
Original link:
https://doi.
org/10.
1038/s41586-022-05440-3
Platemaker: Eleven
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