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Complement activation in chromosome 13 dementias. Similarities with Alzheimer's disease
Agueda Rostagno1, Tamas Revesz, Tammaryn Lashley
1Department of Pathology, School of Medicine, New York University, 550 First Avenue, New York, NY 10016, USA. rostaa02@popmail.med.nyu.edu
Insights
Familial British and Danish dementias involve brain inflammation similar to Alzheimer's disease. Amyloid peptides in these conditions activate the complement system, contributing to neurodegeneration.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Familial British dementia (FBD) and familial Danish dementia (FDD) are chromosome 13 dementias.
- These conditions exhibit neurodegeneration and cerebrovascular amyloidosis, similar to Alzheimer's disease (AD).
- Amyloid peptides (ABri, ADan, Abeta) in these diseases are associated with neuroinflammation.
Purpose of the Study:
- To investigate the role of the complement system in the pathogenesis of FBD and FDD.
- To compare the complement-activating properties of ABri and ADan peptides with Abeta.
Main Methods:
- Immunohistochemistry on FBD and FDD brain sections.
- Hemolytic assays and ELISA to detect complement activation products.
- Binding assays for C1q interaction with amyloid peptides.
Main Results:
- Complement activation components (classical and alternative pathways, membrane attack complex) were found in FBD and FDD brains.
- ABri and ADan fully activated the complement cascade, comparable to Abeta1-42.
- ABri and ADan bound C1q with high affinity, initiating activation primarily via the classical pathway.
Conclusions:
- Amyloid peptides in FBD and FDD activate the complement system, suggesting a role in disease pathogenesis.
- Chronic inflammation driven by amyloid peptides may contribute to neurodegeneration in FBD, FDD, and other neurodegenerative diseases.
Abstract:
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.