Evidence of a role for lactadherin in Alzheimer's disease.
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 beta-peptide (Abeta). 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 Abeta deposition. Using surface plasmon resonance, we observed a direct protein-protein interaction between recombinant lactadherin and Abeta 1-42 peptide in vitro. Lactadherin deficiency or its neutralization using specific antibodies significantly prevented Abeta 1-42 phagocytosis by murine and human macrophages. In conclusion, lactadherin plays an important role in the phagocytosis of Abeta 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.
Boddaert
Jacques
J
Institut National de la Santé et de la Recherche Médicale, Centre de Recherche Cardiovasculaire Lariboisière, Paris, France.
Kinugawa
Kiyoka
K
Lambert
Jean-Charles
JC
Boukhtouche
Fatiha
F
Zoll
Joffrey
J
Merval
Régine
R
Blanc-Brude
Olivier
O
Mann
David
D
Berr
Claudine
C
Vilar
José
J
Garabedian
Béatrice
B
Journiac
Nathalie
N
Charue
Dominique
D
Silvestre
Jean-Sébastien
JS
Duyckaerts
Charles
C
Amouyel
Philippe
P
Mariani
Jean
J
Tedgui
Alain
A
Mallat
Ziad
Z
D000367:Age Factors; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism; D008894:Milk Proteins / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010587:Phagocytosis / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020349:Surface Plasmon Resonance
D016229:Amyloid beta-Peptides; D000954:Antigens, Surface; C098942:MFGE8 protein, human; D008894:Milk Proteins