Midkine as a factor to counteract the deposition of amyloid β-peptide plaques: in vitro analysis and examination in knockout mice

A surface plasmon assay was performed to determine the affinity of midkine for amyloid β-peptide. The deposition of amyloid β-peptide was compared in the brain of wild-type and midkine-deficient mice. An effect of midkine to microglias was examined by cell migration assay.Midkine bound to amyloid β-peptide with the affinity of 160 nM. The C-terminal half bound to the peptide more strongly than the N-terminal half, and heparin inhibited midkine from binding to the peptide. Pleiotrophin, which has about 50% sequence identity with midkine also bound to amyloid β-peptide. The deposition of amyloid β-peptide plaques in the cortex and hippocampus was more intense in 15-month-old midkine-deficient mice, compared to the corresponding wild-type mice. Midkine promoted migration of microglias in culture.These results are consistent with the view that midkine attenuates the deposition of amyloid β-peptide plaques, and thus progression of Alzheimer's disease, by direct binding and also by promoting migration of microglias.An accumulation of amyloid β-peptide (Aβ) in plaques in brain tissue has been proposed to be the primary cause of the neurodegeneration in patients with Alzheimer's disease [1,2]. This view is supported by findings that anti-Aβ antibodies prevent or reverse the disease in mouse models of Alzheimer's disease [1,3,4], although clinical trials of anti- Aβ antibodies did not give expected results [5,6]. Therefore, factors affecting the accumulation of Aβ plaques in brain tissue are important to the treatment and prevention of Alzheimer's disease. This paper primarily examines the role of midkine, a heparin-binding cytokine [7-9], in the deposition of Aβ plaques in the mouse brain.Midkine promotes neurite outgrowth [10], the survival of various cells including neurons [11-13] and the migration of inflammatory leukocytes [14,15] and neurons [16]. Midkine is involved in pathogenesis of malignant tumors [17] and diseases with immunological backgrounds [14,15,18-20] as