Identification of CD40 ligand in Alzheimer's disease and in animal models of Alzheimer's disease and brain injury.
Chronic neuroinflammatory processes including glial activation may play a role in the pathogenesis of Alzheimer's disease (AD). The immune and inflammatory mediator CD40 ligand (CD40L) can augment the activation of cultured microglia by amyloid beta-protein (Abeta) and promote neuron death. We investigated whether CD40L is increased in AD and in animal models of AD and neuroinflammation. In the frontal cortex of elderly, non-AD controls, CD40L immunoreactivity was found in the glial limiting membrane, astrocytes, and vascular profiles in gray and white matter. In AD, intense CD40L immunoreactivity occurred in hypertrophied astrocytes throughout the frontal cortex. The majority of CD40L-immunoreactive astrocytes in the gray matter occurred within, or at the periphery of, Abeta(1-42)-immunoreactive plaques. A semiquantitative analysis revealed a three-fold elevation in the number of CD40L-immunoreactive astrocytes in AD compared to controls. The cortex and hippocampus from 6 and 12 month-old amyloid precursor protein/presenilin 1 transgenic mice exhibited numerous neuritic plaques and CD40L-positive astrocytes, which were not detected in non-transgenic controls. In adult rats, little or no CD40L staining occurred in astrocytes of the intact brain, whereas intrastriatal excitotoxic or stab wound lesions produced a strong CD40L immunoreactivity that was more segregated than glial fibrillary acidic protein. These findings indicate that astrocytes are the predominant source of CD40L in brain, and are consistent with the proposed role of CD40L-mediated neurotoxic inflammation in AD.
Calingasan
Noel Y
NY
Neuroscience Research, Maryland Research Laboratories, Otsuka Maryland Research Institute, Rockville, MD 20850, USA. noelc@otsuka.com
Erdely
Holly A
HA
Altar
C Anthony
CA
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001930:Brain Injuries / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D017378:Quinolinic Acid / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D019013:CD40 Antigens; D005904:Glial Fibrillary Acidic Protein; D023201:CD40 Ligand; D017378:Quinolinic Acid