If aggregates of the sticky amyloid-β can contribute to the pathology of Alzheimer’s disease (AD), then maybe unsticking them will help reverse the process. Far-fetched? Luigi Bergamaschini and colleagues have already demonstrated that anticoagulants such as heparin can attenuate the inflammatory and toxic effects of Aβ in vitro (see Bergamaschini et al., 2002). Now, in the April 28 Journal of Neuroscience, they extend this observation to an in-vivo model of AD.

Bergamaschini, from the University of Milan, together with Maria Grazia De Simoni, from the Mario Negri Institute for Pharmacological Research, also in Milan, administered the low molecular weight heparin enoxaparin to APP23 mice, which overexpress human amyloid precursor protein. The authors chose enoxaparin because of the high risk of bleeding associated with unfractionated heparin. In addition, heparins are known to bind to a short amino acid stretch in amyloid β (residues 13-16).

Bergamaschini treated 12-month-old APP23 mice with six international units of enoxaparin three times a week for six months. When he examined these animals using a monoclonal antibody to amino acids 17-24 of human Aβ, he found that they had much fewer and smaller amyloid deposits in their neocortex than did untreated mice. The data showed about a threefold reduction in plaque load (number and surface area). Quantification of extracted Aβ1-40 revealed a similar reduction, from an average of 45 pg/mg of Aβ1-40 in saline-treated animals, to 20 pg/mg in animals treated with enoxaparin. This reduction in plaque load correlated with a reduction in the number of activated astrocytes, as judged by morphology, size, and number of GFAP-positive cells surrounding the Aβ deposits. The authors did not correlate these data to changes in cognition, because at one year old these animals do not suffer from significant cognitive impairment.

So how does a heparin help these mice? In-vitro experiments provide some clues. To test if enoxaparin can attenuate Aβ toxicity, Bergamaschini added both molecules, either alone or in combination, to PC12 cells. Adding just Aβ1-40 resulted in a loss of about 90 percent of the cells, while enoxaparin alone had no effect on viability. But the heparin prevented Aβ-induced loss of cell viability in a dose-dependent manner. At the highest concentration used, 10 mM, it protected fully.

But whether this direct protection from Aβ toxicity is relevant to the in-vivo observations is unclear. As the authors point out, it is unknown whether low molecular weight heparins such as enoxaparin, can pass the blood-brain barrier. Other possibilities are that the heparin acts as a peripheral sink, drawing Aβ from the brain (this is not unprecedented, see ARF related news story on peripheral antibodies leaching Aβ from mouse brain), or that it inhibits complement activation, thus reducing inflammatory responses.

Significantly, this drug is used as an anticoagulant in humans. So epidemiological data could reveal a protective effect against dementia.—Tom Fagan.

Reference:
Bergamaschini L, Rossi E, Storini C, Pizzimenti S, Distaso M, Perego C, De Luigi A, Vergani C, and De Simoni MG. Peripheral treatment with enoxaparin, a low molecular weight heparin, reduces plaques and β-amyloid accumulation in a mouse model of Alzheimer’s disease. J. Neurosci. 2004 April 28;24:4181-4186. Abstract

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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:
    1. Kisilevsky R, Lemieux LJ, Fraser PE et al. Arresting amyloidosis in vivo using small-molecule anionic sulphonates or sulphates: implications for Alzheimer's disease [see comments]. Nat. Med. 1995;1:143-148. Abstract

    2. Gervais F, Chalifour R, Garceau D et al. Glycosaminoglycan mimetics: a therapeutic approach to cerebral amyloid angiopathy. Amyloid. 2001;8 Suppl 1:28-35. Abstract

    3. Winkler DT, Bondolfi L, Herzig MC et al. Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J. Neurosci. 2001;21:1619-1627. Abstract

    4. Fryer JD, Taylor JW, DeMattos RB et al. Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein transgenic mice. J. Neurosci. 2003;23:7889-7896. Abstract

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References

News Citations

  1. Two Ways to Attack Amyloid: Metal Chelator and Antibody

Paper Citations

  1. . Heparin attenuates cytotoxic and inflammatory activity of Alzheimer amyloid-beta in vitro. Neurobiol Aging. 2002 Jul-Aug;23(4):531-6. PubMed.
  2. . 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.

Further Reading

Papers

  1. . 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.

Primary Papers

  1. . 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.