CD40 ligation mediates plaque-associated tau phosphorylation in beta-amyloid overproducing mice.
Neuritic dystrophy with amyloid burden and neurofibrillary tangles are pathological hallmarks of Alzheimer's disease. Genetic disruption of CD40 or CD40L alleviates amyloid burden, astrocytosis, and microgliosis in transgenic animal models of Alzheimer's disease. It has been reported that phosphorylated tau-positive dystrophic neurites are observed in transgenic mice over-expressing human mutant beta-amyloid precursor protein (Tg2576). Here, we studied the pattern of phosphorylated tau (labeled with AT8, CP13, PG5, and PHF1 antibodies) and plaques using immunohistochemical techniques. Phosphorylated tau-positive dystrophic neurites were exclusively associated with Congo red-positive plaques as previously reported. Further, we show that CD40L or CD40 deficiency reduces the mean ratio of dystrophic neurite area to congophilic plaque area and the level of expression of cdk5 and p35/p25 in mice. In addition, we show that in a human neuroblastoma cell line treated with CD40L, cdk5 and p35/p25 are increased. Together, our data suggest that CD40-CD40L interaction has an effect on tau phosphorylation independent of beta-amyloid pathology, and that this effect may occur through a decrease of cdk5 and p35/p25.
Laporte
Vincent
V
The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA. vlaporte@rfdn.org
Ait-Ghezala
Ghania
G
Volmar
Claude-Henry
CH
Ganey
Christopher
C
Ganey
Nowell
N
Wood
Marcie
M
Mullan
Michael
M
D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D019013:CD40 Antigens / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D000090266:Chromobox Protein Homolog 5; D004396:Coloring Agents; D003224:Congo Red; D051360:Cyclin-Dependent Kinase 5 / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016501:Neurites / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010770:Phosphotransferases / Q000187:drug effects / Q000378:metabolism; D058225:Plaque, Amyloid / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C000715594:CBX5 protein, human; D019013:CD40 Antigens; C492236:Cdk5r1 protein, mouse; D004396:Coloring Agents; D016875:tau Proteins; D000090266:Chromobox Protein Homolog 5; D023201:CD40 Ligand; D003224:Congo Red; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse