Wagner J, Degenhardt K, Veit M, Louros N, Konstantoulea K, Skodras A, Wild K, Liu P, Obermüller U, Bansal V, Dalmia A, Häsler LM, Lambert M, De Vleeschouwer M, Davies HA, Madine J, Kronenberg-Versteeg D, Feederle R, Del Turco D, Nilsson KP, Lashley T, Deller T, Gearing M, Walker LC, Heutink P, Rousseau F, Schymkowitz J, Jucker M, Neher JJ. Medin co-aggregates with vascular amyloid-β in Alzheimer's disease. Nature. 2022 Dec;612(7938):123-131. Epub 2022 Nov 16 PubMed.

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  1. This interesting study, suggesting that medin promotes vascular amyloid accumulation in AD, expands on the authors’ and others’ previous work. Using two mouse models of Aβ amyloidosis, and bolstered by human data and structural data, the authors have achieved a tour de force. However, this study brings up several questions that remain to be answered.

    The authors’ data suggests that medin generated by vascular smooth-muscle cells, and possibly other cells of the neurovascular unit, could play a role in accelerating Aβ pathology and CAA, based on their immunostaining and RNA-Seq analysis. But, how medin interacts with Aβ to promote fibrilization remains still to be investigated. It will be also important to determine which cells are responsible for medin expression and its interaction with Aβ, as this information will be helpful in identifying targets for therapeutic interventions. And, importantly, what would be the effect of medin load on cognitive function?

    Additional work is warranted to tease out the details of medin function and mechanism in relation to amyloid pathology and cognitive decline.

    View all comments by Kassandra Kisler

  2. I think this is a very nice paper and shows good evidence that medin does influence CAA formation and would be a potential novel target for CAA treatment.

    The effect of knocking out medin on CAA is not nearly as strong as knocking out ApoE, which, in similar models, blocks CAA formation completely.  However, there may be advantages in targeting medin and further studies to assess this are warranted.

    View all comments by David Holtzman

  3. This very interesting article points to the 50-amino-acid peptide, medin, as a candidate cofactor in promoting Aβ deposition, particularly in cerebral blood vessels, i.e., cerebral amyloid angiopathy (CAA). The suggestion, based on ROSMAP data, that the precursor protein of medin, MFGE8, is upregulated in cerebral smooth muscle and endothelial cells from Alzheimer’s disease brains is particularly intriguing, because it suggests medin expression is localized to the cerebral blood vessels.

    Disentangling causes from effects of CAA and of Alzheimer’s disease can be very challenging and it is not yet clear that medin will fall into the cause rather than the effect category. Nonetheless, the experiments in this paper form a strong foundation for further study of this potentially important contributor to the pathogenesis of these two diseases.

    View all comments by Steven Greenberg

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