Researchers have ascertained that excessive amounts of complement C3, an essential immune protein that increases with aging, are responsible for causing dementia in a mouse model.
A necessary complement
The complement system is a key immune system component that is involved in removing misfolded proteins, infectious diseases, and various cellular fragments from the brain [1]. Deficiencies in C3 or its receptor lead to severe cognitive deficits in model mice [2]. However, another study found that C3-deficient mice, unlike their normal counterparts, do not suffer from age-related deterioriation of the hippocampus [3].
Just like in monkeys and mice, C3 increases with age in human beings [4]. In frontotemporal dementia patients, increased C3 is correlated with decreased volume of the frontal lobe [5]. Those studies led these researchers to inquire into the fundamental biochemistry of how and why a critical immune system protein might lead to damage.
Too much of a good thing
The researchers’ first experiment used genetically engineered mice that overexpress C3. After confirming that their modification worked, they performed behavioral tests on 16 C3-overexpresing mice and an equal number of wild-type controls. The C3-overexpressing mice were less likely to examine novel objects and showed a reduced ability to learn fear responses, and they performed worse on a rotarod test. These negative effects were only found in mature mice; 1-month-old mice did not seem affected by this overexpression.
These findings were confirmed with a more direct examination of brain synapses. PSD95, a biomarker of postsynaptic density, and NeuN, a biomarker of neuronal activity, were both decreased in the C3-overexpressing mice compared to the control group, although these effects appared to be limited to a specific area of the hippocampus. The number of astrocytes was also significantly increased in the C3-overexpressing mice, and dopamine release was decreased.
These negative effects were found to be related to impaired insulin signaling. Diabetes and obesity have been found to lead to cognitive problems [6], and a lack of functional insulin receptors has been found to make Alzheimer’s worse in model mice [7].
C3 is naturally cleaved into C3a and C3b. Introducing more C3a to astrocytes in cellular culture impaired insulin signaling, decreasing their survivability. It also had negative effects on the mitochondria: reactive oxygen species (ROS) were increased, while fundamental genes in the mitochondria became less strongly expressed. Matching the murine results, dopamine release was also significantly decreased.
A path to a potential treatment
The researchers then utilized SAMP8 mice, which age faster than normal mice and have accompanying cognitive decline. This was found to be accompanied by an increase in C3. Introucing C3 antibodies directly into the brains of these mice improved their performance on some memory tests, including the Y maze test, compared to a control group; however, it had no significant effects on the Barnes maze test, which examines spatial learning and memory.
This study did not examine wild-type mice, nor did it test a therapy that could be potentially used in human beings; the C3 antibody was introduced through a brain cannula. However, it did set the stage for further studies. If this immune system component is responsible for significant cognitive decline in older people, it may be possible to treat it directly or to determine and treat the root cause of its increase.
Literature
[1] Stephan, A. H., Barres, B. A., & Stevens, B. (2012). The complement system: an unexpected role in synaptic pruning during development and disease. Annual review of neuroscience, 35(1), 369-389.
[2] Westacott, L. J., Haan, N., Evison, C., Marei, O., Hall, J., Hughes, T. R., … & Gray, W. P. (2021). Dissociable effects of complement C3 and C3aR on survival and morphology of adult born hippocampal neurons, pattern separation, and cognitive flexibility in male mice. Brain, Behavior, and Immunity, 98, 136-150.
[3] Shi, Q., Colodner, K. J., Matousek, S. B., Merry, K., Hong, S., Kenison, J. E., … & Lemere, C. A. (2015). Complement C3-deficient mice fail to display age-related hippocampal decline. Journal of Neuroscience, 35(38), 13029-13042.
[4] Cribbs, D. H., Berchtold, N. C., Perreau, V., Coleman, P. D., Rogers, J., Tenner, A. J., & Cotman, C. W. (2012). Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. Journal of neuroinflammation, 9, 1-18.
[5] van der Ende, E. L., Heller, C., Sogorb-Esteve, A., Swift, I. J., McFall, D., Peakman, G., … & Seelaar, H. (2022). Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study. Journal of neuroinflammation, 19(1), 217.
[6] Kleinridders, A., Ferris, H. A., Cai, W., & Kahn, C. R. (2014). Insulin action in brain regulates systemic metabolism and brain function. Diabetes, 63(7), 2232-2243.
[7] Chen, W., Huang, Q., Lazdon, E. K., Gomes, A., Wong, M., Stephens, E., … & Kahn, C. R. (2023). Loss of insulin signaling in astrocytes exacerbates Alzheimer-like phenotypes in a 5xFAD mouse model. Proceedings of the National Academy of Sciences, 120(21), e2220684120.
