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The Journal of Neuroscience, April 28, 2004, 24(17):4181-4186; doi:10.1523/JNEUROSCI.0550-04.2004

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Peripheral Treatment with Enoxaparin, a Low Molecular Weight Heparin, Reduces Plaques and -Amyloid Accumulation in a Mouse Model of Alzheimer's Disease

Luigi Bergamaschini,^1 * Emanuela Rossi,¹ Claudio Storini,² Simone Pizzimenti,² Maria Distaso,² Carlo Perego,² Ada De Luigi,² Carlo Vergani,¹ and Maria Grazia De Simoni^2 *

¹Department of Internal Medicine, Ospedale Maggiore, Instituto di Ricovero e Cura a Carattere Scientifico, University of Milan, 20122 Milan, Italy, and ²Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milan d015, Italy

We investigated the effect of long-term, peripheral treatment with enoxaparin, a low molecular weight heparin, in transgenic mice overexpressing human amyloid precursor protein₇₅₁. Enoxaparin (6 IU per mouse intraperitoneally, three times a week for 6 months) significantly lowered the number and the area occupied by cortical -amyloid deposits and the total -amyloid (1-40) cortical concentration. Immunocytochemical analysis of glial fibrillary acid protein-positive cells showed that enoxaparin markedly reduced the number of activated astrocytes surrounding -amyloid deposits. In vitro, the drug dose-dependently attenuated the toxic effect of -amyloid on neuronal cells. Enoxaparin dose-dependently reduced the ability of -amyloid to activate complement and contact systems, two powerful effectors of inflammatory response in AD brain. By reducing the -amyloid load and cytotoxicity and proinflammatory activity, enoxaparin offers promise as a tool for slowing the progression of Alzheimer's disease.

Key words: Alzheimer; amyloid; A; binding agent; low molecular weight heparin; APP23 mouse; inflammation; complement system; kinin system; heparin

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Received Nov 23, 2003; revised March 20, 2004; accepted March 21, 2004.

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