Complement-Mediated Events in Alzheimer's Disease: Mechanisms and Potential Therapeutic Targets

Abstract

An estimated 5.7 million Americans suffer from Alzheimer's disease in the United States, with no disease-modifying treatments to prevent or treat cognitive deficits associated with the disease. Genome-wide association studies suggest that an enhancement of clearance mechanisms and/or promotion of an anti-inflammatory response may slow or prevent disease progression. Increasing awareness of distinct roles of complement components in normal brain development and function and in neurodegenerative disorders align with complement-mediated responses, and thus, thorough understanding of these molecular pathways is needed to facilitate successful therapeutic design. Both beneficial and detrimental effects of C1q as well as contributions to local inflammation by C5a-C5aR1 signaling in brain highlight the need for precision of therapeutic design. The potential benefit of β-amyloid clearance from the circulation via CR1-mediated mechanisms is also reviewed. Therapies that suppress inflammation while preserving protective effects of complement could be tested now to slow the progression of this debilitating disease.

Figure 1:. Complement-mediated functions change with disease progression.

Early disease (Phase 1): C1q expression is upregulated by “injury” independently of other complement cascade proteins. C1q binds apoptotic neurons and neuronal blebs, thereby enhancing phagocytosis by microglia (pink) while also suppressing inflammatory response in the absence of other PAMPs/DAMPs. Phase 2: The complement cascade is chronically activated as fAß and other activators accumulate. C1r, C1s, C4, and C3 synthesis is induced in response to more local damage, while the complement regulators C1-INH and C4BP are not comparatively upregulated. Generated C3b/iC3b covalently links to fAβ and may lead to phagocytosis. However, in Phase 3, C5a is also generated, diffuses from the plaque, engages C5aR1 on microglia and induces chemotactic activity recruiting microglia to the plaques. fAβ binds to microglial TLR receptors (or others) inducing a synergistic response including pro-inflammatory cytokine secretion and reactive oxygen species production. Since large fAβ plaques are not efficiently cleared, a chronic inflammatory environment develops contributing to greater neuronal damage conducive to more fAβ production and ultimately neuronal dysfunction and death. The contribution of all these events to AD onset and progression in humans remains to be determined.

Figure 2:. Beneficial complement-mediated functions in the brain are retained in the presence of C5aR1 antagonists.

A specific C5aR1 antagonist (inhibitor, INH) will prevent induction of detrimental pro-inflammatory responses to chronic fibrillar Aβ via blocking C5a-induced microglia responses (and possibly induction of A1 astrocytes), as well as block C5a-induced neuronal apoptosis. The antagonist will not affect the direct interaction of C1q with neurons that promotes survival and resistance to fAβ induced death (left), nor the enhancement of microglial uptake of apoptotic cells and neuronal blebs with suppression of inflammatory cytokine release (right). CR3 will remain functional mediating phagocytosis by engaging iC3b and C3b bound to Aβ, apoptotic cells or other debris (right). C5aR2 would be unaffected and can act as a scavenger of C5a to contribute to the suppression of pro-inflammatory responses (left and right). Not pictured: Formation of membranolytic C5b-9 on pathogens will not be affected.