Amyloid‐β Pathology Exacerbates Aging‐Induced Dysregulation of C1q Expression in Cortical Neurons

Abstract

AbstractBackgroundAging, even in the absence of age‐related pathologies such as Alzheimer’s disease (AD), is associated with a loss of neuronal function and structure, and cognitive decline. An initiator of the classical complement cascade, C1q, which enhances the immune response in the periphery, has been shown to mediate synaptic pruning in the developing brain (Stevens et al., 2007). It has been hypothesized that this cascade may be implicated in the cognitive decline associated with aging, as well as neurodegenerative diseases, such as AD.MethodIn this study, magnetic‐activated cell sorting (MACS), a cell separation technology based on the use of antibody‐conjugated beads, was utilized to isolate neurons from the whole cortex tissue dissociations of wild‐type (Thy1‐GFP) and AD model (APPNL‐G‐F‐GFP) mice at different life stages: 3 months (young adult), 6 months (adult), 12 months (middle‐aged adult), and > 21 months of age (aged). Droplet‐digital polymerase chain reaction (ddPCR), an advanced PCR technology with higher accuracy and consistency than traditional PCR methods, and Simple Western, an automated western blot system, were utilized to quantify the expression of C1QA and C1q, respectively, in isolated cortical neurons.ResultThere is a significant aging‐induced increase in C1q levels in cortical neurons of both wild‐type and AD model aged mice. Interestingly, in middle‐aged AD mice, in which the deposition of amyloid‐β plaques is already severe, the levels of C1q are significantly elevated compared with wild‐type mice, and the expression levels are comparable to that of aged mice of both genotypes.ConclusionThese findings support the notion that the initiation of the classical complement cascade by cortical neurons is upregulated with healthy aging, and this aging‐induced upregulation is accelerated by amyloid‐β pathology.