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Perforant path transection induces complement C9 deposition in hippocampus
S a Johnson1, C S Young-Chan, N J Laping
1Neurogerontology Division, Andrus Gerontology Center, University of Southern California, Los Angeles, 90089-0191, USA.
Insights
The complement system, including C9 and clusterin, is involved in brain injury responses and Alzheimer disease (AD). Complement proteins were found in damaged brain areas but did not appear to cause neuron death in this study.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Alzheimer disease (AD) is characterized by amyloid plaques and complement system activation.
- Complement system proteins and mRNAs are upregulated in AD-affected brain regions.
Purpose of the Study:
- To investigate complement protein expression in a rodent model of AD-related brain injury.
- To examine the role of complement in neuronal apoptosis and synaptic changes following injury.
Main Methods:
- Utilized a rat model with perforant path transection to mimic AD-related neuronal degeneration.
- Employed immunostaining to detect complement C9 and clusterin (SGP-2) in brain tissue.
- Assessed neuronal apoptosis and localization of complement proteins.
Main Results:
- Extracellular C9 deposition was observed in wounded brain areas and hippocampus, peaking at 1 day and resolving by 14 days post-lesion.
- Complement C9 was not found in apoptotic neurons, suggesting it does not induce apoptosis in this model.
- Extracellular and intracellular C9, along with clusterin, were detected in specific hippocampal regions associated with synaptic loss and degeneration.
Conclusions:
- The complement system is generally involved in the brain's response to injury.
- Findings support a role for the complement system in Alzheimer disease pathology and brain injury.
Abstract:
The presence of complement system proteins in amyloid plaques and the up-regulation of several complement mRNAs in neurons and glial cells in affected brain regions during Alzheimer disease (AD) provided a basis for further examination of complement protein expression in a rodent lesion model of AD. Perforant path transection in rats was used as a model for the degeneration of entorhinal cortex (EC) layer II neurons and the consequent deafferentation of the hippocampus that occurs during AD. Immunostaining for C9, a key terminal component of the complement cascade membrane attack complex (MAC), showed extracellular C9 deposition in parenchyma around the EC wound and in hippocampus as early as 1 day, and disappeared by 14 days postlesion. Apoptosis of EC layer II neurons was seen and was presumably due to severing of their axonal projections to the hippocampus by the transection lesion. However, apoptotic EC layer II neurons were not immunostained by anti-rat C9 antibody, suggesting complement was not involved in inducing apoptosis. In the deafferented hippocampus, extracellular C9 immunostaining was localized to the dentate gyrus middle molecular layer, a region of synaptic loss, dendritic degeneration, and early synaptogenesis. In addition, intracellular C9 immunostaining was seen only in select hippocampal interneurons. Dentate gyrus granule neurons and pyramidal neurons were not C9 immunostained. Clusterin (SGP-2), a soluble inhibitor of the MAC that is up-regulated in AD, was also detected in the wound area (extracellular), the dentate gyrus middle molecular layer (extracellular), and intracellularly in scattered hippocampal interneurons. The data support the hypothesis that the complement system generally participates in responses to brain injury, as well as in AD.