Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice.
We have shown that interaction of CD40 with CD40L enables microglial activation in response to amyloid-beta peptide (Abeta), which is associated with Alzheimer's disease (AD)-like neuronal tau hyperphosphorylation in vivo. Here we report that transgenic mice overproducing Abeta, but deficient in CD40L, showed decreased astrocytosis and microgliosis associated with diminished Abeta levels and beta-amyloid plaque load. Furthermore, in the PSAPP transgenic mouse model of AD, a depleting antibody against CD40L caused marked attenuation of Abeta/beta-amyloid pathology, which was associated with decreased amyloidogenic processing of amyloid precursor protein (APP) and increased circulating levels of Abeta. 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.
Tan
Jun
J
The Roskamp Institute, Department of Psychiatry, University of South Florida, 3515 East Fletcher Avenue, Tampa, Florida 33613, USA.
Town
Terrence
T
Crawford
Fiona
F
Mori
Takashi
T
DelleDonne
Anthony
A
Crescentini
Robert
R
Obregon
Demian
D
Flavell
Richard A
RA
Mullan
Michael J
MJ
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005260:Female; D005911:Gliosis / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D058225:Plaque, Amyloid / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D019013:CD40 Antigens; D023201:CD40 Ligand