The Importance of Complement-Mediated Immune Signaling in Alzheimer’s Disease Pathogenesis

Abstract

As an essential component of our innate immune system, the complement system is responsible for our defense against pathogens. The complement cascade has complex roles in the central nervous system (CNS), most of what we know about it stems from its role in brain development. However, in recent years, numerous reports have implicated the classical complement cascade in both brain development and decline. More specifically, complement dysfunction has been implicated in neurodegenerative disorders, such as Alzheimer’s disease (AD), which is the most common form of dementia. Synapse loss is one of the main pathological hallmarks of AD and correlates with memory impairment. Throughout the course of AD progression, synapses are tagged with complement proteins and are consequently removed by microglia that express complement receptors. Notably, astrocytes are also capable of secreting signals that induce the expression of complement proteins in the CNS. Both astrocytes and microglia are implicated in neuroinflammation, another hallmark of AD pathogenesis. In this review, we provide an overview of previously known and newly established roles for the complement cascade in the CNS and we explore how complement interactions with microglia, astrocytes, and other risk factors such as TREM2 and ApoE4 modulate the processes of neurodegeneration in both amyloid and tau models of AD.

Beneficial versus Detrimental Effects of Complement-Microglial Interactions in Alzheimer’s Disease

“…Furthermore, C3 released from astrocytes also interacts with C3aR on microglia and mediates Aβ pathology and neuroinflammation. Since dendritic and synaptic loss in neurons is caused by NFκB/C3/C3aR signaling, it seems reasonable that cognition is improved in APP/PS1 mice administered a C3aR antagonist (Lian et al, 2015) (Batista et al, 2024). These studies provide evidence that unique neuron-glia signaling pathways link Aβ pathology with synaptic abnormalities and neuronal hyperexcitability.…”

“…In the context of AD, microglial priming is increasingly being proposed as a prerequisite process when chronic low-level stimuli (such as systemic inflammation and aging) cause naive microglia to assume an altered state, resulting in an enhanced or inappropriate inflammatory reaction in response to repeated pathological stimulation (Perry & Holmes, 2014). Alterations of microglial phenotype in AD leads to activation of inflammasome signaling, the release of excessive inflammatory cytokines, which in turn promotes neurotoxicity and excessive microglial synapse elimination (Hong et al, 2016b) (Venegas et al, 2017) (Batista et al, 2024). Findings confirm that neuroinflammation is an ongoing process that does not resolve on its own and is regarded as a critical driver of the AD (Heneka et al, 2015).…”

“…Although the mechanisms, involved in the contribution of complement cascade as well as complement-related genes to AD pathogenesis are under investigation, findings on human brain tissue and animal models demonstrate that complement regulatory dysfunction plays a significant role in the development of AD (Batista et al, 2024). Post-mortem studies of AD brains demonstrated a dramatic increase in the activation of all complement components (Reichwald et al, 2009) (Maier et al, 2008).…”

“…Indeed, C1q, as well as TNF-α and interleukin-1α (IL-1α), released from activated microglia promote astrocytes to change into their reactive pattern, namely A1 astrocytes, which are main producers of complement protein C3 (Liddelow et al, 2017). Complement C3 released from A1-reactive astrocytes accumulates on amyloid plaques, NFTs, and weakened synapses (Batista et al, 2024).…”

The Impact of Anti-Amyloid Immunotherapies on Stroke Care

“…Supporting this hypothesis, a recent study investigating ARIA in a mouse model of AD using the murine equivalent of the anti-amyloid antibody bapineuzumab, 3D6, demonstrated that administering anti-amyloid antibodies triggered the formation of antibody immune complexes with vascular Aβ, in turn activating perivascular macrophages and upregulating genes associated with vascular permeability [ 64 ]. Antibody-mediated complement activation may be an important step in immune cell activation leading to vascular damage and ARIA [ 65 , 66 ]. Modifying these antibodies to minimize complement activation is an area of active investigation.…”