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(American Journal of Pathology. 2007;170:921-929.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060664

Evidence of a Role for Lactadherin in Alzheimer’s Disease

Jacques Boddaert^*, Kiyoka Kinugawa^*, Jean-Charles Lambert, Fatiha Boukhtouche, Joffrey Zoll^*, Régine Merval^*, Olivier Blanc-Brude^*, David Mann, Claudine Berr^¶, José Vilar^*, Béatrice Garabedian, Nathalie Journiac, Dominique Charue^*, Jean-Sébastien Silvestre^*, Charles Duyckaerts^||, Philippe Amouyel, Jean Mariani, Alain Tedgui^* and Ziad Mallat^*

From the Institut National de la Santé et de la Recherche Médicale (INSERM),^* Unit 689, Centre de Recherche Cardiovasculaire Lariboisière, Paris, France; INSERM U508, Epidémiologie des Maladies Chroniques Dégénératives, Institut Pasteur de Lille, Lille, France; the Laboratoire Développement et Vieillissement du Système Nerveux, Unité Mixte de Recherche Neurobiologie de Processus Adaptatifs 7102 Centre National de la Recherche Scientifique and Université Pierre et Marie Curie, Paris, France; INSERM E361,^¶ Epidémiologie et Clinique des Maladies Neurodégénératives, Hôpital La Colombière, Montpellier, France; the Laboratoire de Neuropathologie Raymond Escourolle,|| Groupe Hospitalier Pitié-Salpêtrière, Paris, France; and the Clinical Neuroscience Research Group, University of Manchester, Greater Manchester Neurosciences Centre, Hope Hospital, Salford, United Kingdom

Lactadherin is a secreted extracellular matrix protein expressed in phagocytes and contributes to the removal of apoptotic cells. We examined lactadherin expression in brain sections of patients with or without Alzheimer’s disease and studied its role in the phagocytosis of amyloid ß-peptide (Aß). Cells involved in Alzheimer’s disease, including vascular smooth muscle cells, astrocytes, and microglia, showed a time-related increase in lactadherin production in culture. Quantitative analysis of the level of lactadherin showed a 35% reduction in lactadherin mRNA expression in the brains of patients with Alzheimer’s disease (n = 52) compared with age-matched controls (n = 58; P = 0.003). Interestingly, lactadherin protein was detected in the brains of patients with Alzheimer’s disease and controls, with low expression in areas rich in senile plaques and marked expression in areas without Aß deposition. Using surface plasmon resonance, we observed a direct protein-protein interaction between recombinant lactadherin and Aß 1-42 peptide in vitro. Lactadherin deficiency or its neutralization using specific antibodies significantly prevented Aß 1-42 phagocytosis by murine and human macrophages. In conclusion, lactadherin plays an important role in the phagocytosis of Aß 1-42 peptide, and its expression is reduced in Alzheimer’s disease. Alterations in lactadherin production/function may contribute to the initiation and/or progression of Alzheimer’s disease.

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