The immune system changes with age, a mix of damage and reactions to that damage. Some of those reactions make things better and some are maladaptive, making things worse. Immune cell populations change in size, and immune cells themselves carry burdens of dysfunction, the usual forms of damage and change one might expect from the Strategies for Engineered Negligible Senescence (SENS) view of cellular aging. Immune cell behaviors change in response to both internal shifts and the altered environment they find themselves in, a change in the signaling produced by all of the other cells in the body. Much of this is a matter of chronic inflammation, a sustained activation of the primary triggers that cause the immune system to react in defense of the body. In old age these triggers become constantly active, a maladaptive response to damage and dysfunction in cells through the body.
The complement system is a major component of the innate immune system, a well-mapped collection of circulating signal molecules and their cell surface receptors that acts to call the immune system to action against forms of infection and damage. But one should also consider that the innate immune system is actively involved in tissue maintenance and function beyond defense, and thus any aspect of the immune system likely affects normal tissue function as well. The complement system is in one sense easy to measure, just assess the levels of the various signals. In another sense it is hard to measure; what do specific alterations in signaling actually mean for system-level functions, or functions in the tissues supported by innate immune cells? This has been fairly well studied, as complement dysfunction is implicated in a range of autoimmune conditions, and in aging itself, but firm answers remain challenging here, just as is the case elsewhere in our biochemistry.
Within this context, the authors of today's open access paper show a distinct pattern of differences in complement signaling between older individuals who do and do not go on to develop Alzheimer's disease. This fits with much of the research into the relationship between the innate immune system, particular its inflammatory behavior, and the development of neurodegenerative conditions. To a large degree, the innate immune system of the central nervous system is not the same innate immune system of the rest of the body; the two sides communicate with one another, but the brain has microglia where the rest of the body has macrophages and other cell types. Microglia are similar to macrophages, but with important additions to their portfolio of duties that relate to the maintenance of connections between neurons. A growing body of work implicates the dysfunction and inflammatory behavior of microglia in the onset and progression of neurodegenerative conditions.
The complement system, an essential component of innate immunity, contributes to pathogen clearance, removal of apoptotic cells, and elimination of misfolded proteins. Within the central nervous system (CNS), circulating complement factors are actively involved in neuronal development, synaptic remodeling, and immune surveillance. However, aberrant complement activation is increasingly associated with neuroinflammatory pathologies, including Alzheimer's disease (AD).
We conducted a study involving two cohorts: a longitudinal cohort (n = 235; all cognitively normal at baseline) and a cross-sectional cohort (n = 323; including 53 with AD, 54 with vascular dementia, 51 with Parkinson's disease dementia, 56 with behavioral variant frontotemporal dementia, and 52 with dementia with Lewy bodies). Plasma levels of 14 complement factors were assessed every 2 years over a 10-year follow-up period in the longitudinal cohort and once in the cross-sectional cohort.
In this 10-year follow-up study, complement factors C4, C4b, Factor I, Factor D and Properdin showed progressive deviations from normative aging trajectories exclusively in individuals who later converted to AD. These alterations correlated robustly with established cerebrospinal fluid (CSF) biomarkers, indicating that peripheral complement remodeling reflects AD-specific pathophysiology rather than age-related change. Collectively, these findings establish complement dysregulation as a systemic hallmark of Pre-AD and identify a discrete panel of proteins with potential for early detection and treatment.
View the full article at FightAging
