Nature Neuroscience5, 1288 - 1293 (2002)
Published online: 28 October 2002; | doi:10.1038/nn968
Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice
Jun Tan1, 3, Terrence Town1, 3, Fiona Crawford1, Takashi Mori1, Anthony DelleDonne1, Robert Crescentini1, Demian Obregon1, Richard A. Flavell2
& Michael J. Mullan1
1
The Roskamp Institute, Department of Psychiatry, University of South Florida, 3515 East Fletcher Avenue, Tampa, Florida 33613, USA
2
Howard Hughes Medical Institute, Yale University School of Medicine, 310 Cedar Street, New Haven, Connecticut 06520, USA
3
The first two authors contributed equally to this work
We have shown that interaction of CD40 with CD40L enables microglial activation in response to amyloid- peptide (A), which is associated with Alzheimer's disease (AD)-like neuronal tau hyperphosphorylation in vivo. Here we report that transgenic mice overproducing A, but deficient in CD40L, showed decreased astrocytosis and microgliosis associated with diminished A levels and -amyloid plaque load. Furthermore, in the PSAPP transgenic mouse model of AD, a depleting antibody against CD40L caused marked attenuation of A/-amyloid pathology, which was associated with decreased amyloidogenic processing of amyloid precursor protein (APP) and increased circulating levels of A. Conversely, in neuroblastoma cells overexpressing wild-type human APP, the CD40−CD40L interaction resulted in amyloidogenic APP processing. These findings suggest several possible mechanisms underlying mitigation of AD pathology in response to CD40L depletion, and validate the CD40−CD40L interaction as a target for therapeutic intervention in AD.
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peptide (A
-secretase for generation of A
