Complement activation in chromosome 13 dementias. Similarities with Alzheimer's disease.
Chromosome 13 dementias, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with neurodegeneration and cerebrovascular amyloidosis, with striking neuropathological similarities to Alzheimer's disease (AD). Despite the structural differences among the amyloid subunits (ABri in FBD, ADan in FDD, and Abeta in AD), these disorders are all characterized by the presence of neurofibrillary tangles and parenchymal and vascular amyloid deposits co-localizing with markers of glial activation, suggestive of local inflammation. Proteins of the complement system and their pro-inflammatory activation products are among the inflammation markers associated with AD lesions. Immunohistochemistry of FBD and FDD brain sections demonstrated the presence of complement activation components of the classical and alternative pathways as well as the neo-epitope of the membrane attack complex. Hemolytic experiments and enzyme-linked immunosorbent assays specific for the activation products iC3b, C4d, Bb, and C5b-9 indicated that ABri and ADan are able to fully activate the complement cascade at levels comparable to those generated by Abeta1-42. ABri and ADan specifically bound C1q with high affinity and formed stable complexes in physiological conditions. Activation proceeds approximately 70-75% through the classical pathway while only approximately 25-30% seems to occur through the alternative pathway. The data suggest that the chronic inflammatory response generated by the amyloid peptides in vivo might be a contributing factor for the pathogenesis of FBD and FDD and, in more general terms, to other neurodegenerative conditions.
Rostagno
Agueda
A
Department of Pathology, School of Medicine, New York University, 550 First Avenue, New York, NY 10016, USA. rostaa02@popmail.med.nyu.edu
Revesz
Tamas
T
Lashley
Tammaryn
T
Tomidokoro
Yasushi
Y
Magnotti
Laura
L
Braendgaard
Hans
H
Plant
Gordon
G
Bojsen-Møller
Marie
M
Holton
Janice
J
Frangione
Blas
B
Ghiso
Jorge
J
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D000595:Amino Acid Sequence; D000682:Amyloid / Q000096:biosynthesis / Q000737:chemistry; D001665:Binding Sites; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002882:Chromosomes, Human, Pair 13; D003167:Complement Activation; D051561:Complement C3 Convertase, Alternative Pathway; D003179:Complement C3b / Q000096:biosynthesis; D003181:Complement C4 / Q000096:biosynthesis; D015935:Complement C4b; D015938:Complement Membrane Attack Complex / Q000096:biosynthesis; D003704:Dementia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D006461:Hemolysis; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000096:biosynthesis; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid
D000682:Amyloid; D003181:Complement C4; D015938:Complement Membrane Attack Complex; D000939:Epitopes; D010446:Peptide Fragments; D010455:Peptides; D003179:Complement C3b; D015935:Complement C4b; C032261:complement C4d; D051561:Complement C3 Convertase, Alternative Pathway