Bergamaschini L, Rossi E, Storini C, Pizzimenti S, Distaso M, Perego C, De Luigi A, Vergani C, De Simoni MG. Peripheral treatment with enoxaparin, a low molecular weight heparin, reduces plaques and beta-amyloid accumulation in a mouse model of Alzheimer's disease. J Neurosci. 2004 Apr 28;24(17):4181-6. PubMed.

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  1. The effects of unfractionated (Neurobiol Aging 2002;23:531) and now fractionated heparins on Aß bioactivity (in vitro) and deposition (in vivo) are clearly intriguing, though it remains unclear how to tie these in-vitro and in- vivo findings together. The data are probably most reminiscent of work by Kisilevsky (1) and others highlighting the role of sulphated constituents of the basement membrane in stimulating amyloid formation and bioactivity. The idea of using soluble glycosaminoglycan mimetics to retard progression of AD and cerebral amyloid angiopathy (2) has recently entered into clinical trial. (By way of disclosure: I am the PI of the CAA study, jointly funded by NINDS and the biotech company Neurochem.) The authors note that heparin did not cause hemorrhages in these young (6-month old) APP23 mice. The risk of hemorrhage may be a greater concern, however, when treating older mice--or older people. While young transgenic mice do not develop severe vascular amyloid, Mathias Jucker, David Holtzman, and colleagues have convincingly demonstrated spontaneous intracerebral hemorrhages in aged transgenic mice with advanced cerebral amyloid angiopathy (3,4).

    References:

    Kisilevsky R, Lemieux LJ, Fraser PE, Kong X, Hultin PG, Szarek WA. Arresting amyloidosis in vivo using small-molecule anionic sulphonates or sulphates: implications for Alzheimer's disease. Nat Med. 1995 Feb;1(2):143-8. PubMed.

    Gervais F, Chalifour R, Garceau D, Kong X, Laurin J, Mclaughlin R, Morissette C, Paquette J. Glycosaminoglycan mimetics: a therapeutic approach to cerebral amyloid angiopathy. Amyloid. 2001 Jul;8 Suppl 1:28-35. PubMed.

    Winkler DT, Bondolfi L, Herzig MC, Jann L, Calhoun ME, Wiederhold KH, Tolnay M, Staufenbiel M, Jucker M. Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J Neurosci. 2001 Mar 1;21(5):1619-27. PubMed.

    Fryer JD, Taylor JW, Demattos RB, Bales KR, Paul SM, Parsadanian M, Holtzman DM. Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein transgenic mice. J Neurosci. 2003 Aug 27;23(21):7889-96. PubMed.

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