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Protein deposits in blood vessel walls may cause dementia


Accumulations of insoluble, misfolded, and aggregated proteins are referred to as amyloidosis. The most common human amyloid consists of medin, a 50 amino acid long peptide that is cleaved from lactadherin. This milk protein is also known as MFG-E8 (milk fat globule EGF-like factor-8) and is a membrane glycoprotein that connects smooth muscle cells in the vasculature to the surrounding basement membrane. Medin amyloid is found particularly in the wall of vessels, leads to their stiffening and is detectable in increased amounts in patients with vascular dementia or Alzheimer's disease. It is unclear, however, whether the elevated medin levels are a cause or a consequence of Alzheimer's pathology.


A study by Jessica Wagner and Karoline Degenhardt of Jonas Neher's research group at the Center for Neurodegenerative Diseases in Tübingen, Germany, has now demonstrated that in an Alzheimer's animal model (APP23 mouse), amyloid plaques decrease by half when the MFG-E8-encoding gene is missing. The paper, published in Nature in 2022, convincingly demonstrates that in Alzheimer's animals that develop parenchymal amyloid plaques and vascular disease (cerebral amyloid angiopathy), medin and Aβ-amyloid bind together promoting fibril formation. Moreover, injection of aggregated medin stimulates Aβ-amyloid deposition in the hippocampus of the temporal lobe, whereas knocking out medin almost completely abolishes vascular damage.

To test whether the results were also relevant to humans, the authors detected medin in postmortem brain slices from Alzheimer's patients. Indeed, the peptide fragment was abundant in vascular amyloid but - unlike in mice - did not occur in the parenchymal amyloid plaques of the brain.


The interaction of medin and Aβ may be explained by the fact that human medin contains a sequence that has homologies to Aβ and is located in the aggregation-prone C-terminal region of the peptide. Further evidence for a link between medin and Alzheimer's comes from data from 566 patients showing that higher MFG-E8 levels correlate with greater cognitive decline (also accounting for the expression of plaque and tau pathology). Thus, the pathogenesis of AD appears to have an important vascular component associated with medin deposition.


Targeting medin could therefore help preserve brain function during aging and slow Alzheimer's disease. Jonas Neher considers medin to be a promising pharmacological target. Since medin has no other known physiological function, its elimination should not cause any side effects, and because of its localization in blood vessels, it should also be readily accessible to drugs. In any case, the authors of the paper have already produced mice with humanized medin and are currently investigating whether immunotherapy could eliminate these deposits. In addition, improved dementia diagnostics using new medin-coupled ligands (PET tracers) to detect amyloid angiopathy would also be possible.


Reference:


Wagner J, Degenhardt K, Veit M, ..., Jucker M, Neher JJ (2022) Medin co-aggregates with vascular amyloid-β in Alzheimer's disease. Nature 612:123


Image credit: iStock/Rasi Bhadramani

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