Skip to main content
eScholarship
Open Access Publications from the University of California

Scholarly Works (66 results)

  • Article
  • Peer Reviewed
UC Irvine Previously Published Works (2020)
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.
    Cover page: Complement-Mediated Events in Alzheimer's Disease: Mechanisms and Potential Therapeutic Targets.
    • Thesis
    • Peer Reviewed
    UC Irvine Electronic Theses and Dissertations (2017)

    C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, is primarily expressed on cells of the myeloid lineage, and to a lesser extent on endothelial cells and neurons in brain. Previous work demonstrated that a C5aR1 antagonist, PMX205, decreased amyloid pathology and suppressed cognitive deficits in Alzheimer disease (AD) mouse models. However, the cellular mechanisms of this protection have not been definitively demonstrated. Here, we show that C5a can induce neuronal cell death. Both pharmacologic and genetic data indicate that C5aR1 is required for the C5a-induced decrease of neuron MAP-2. Additionally, in the context of AD, we show that increased neuronal damage is caused by the addition of C5a to neurons treated with fAβ, and can be blocked by the C5aR1 antagonist, PMX53.To understand the role of microglial C5aR1 in an AD mouse model, CX3CR1GFP and CCR2RFP reporter mice were bred to C5aR1 sufficient and knockout wild type and Arctic mice. Microglia (GFP-positive, RFP-negative) and infiltrating monocytes (GFP and RFP-positive) were sorted for transcriptome analysis at 2, 5, 7 and 10 months of age. Immunohistochemical analysis showed no CCR2+ monocytes/macrophages near the plaques in the Arctic brain with or without C5aR1. RNA-seq analysis on microglia from these mice identified inflammation related genes as differentially expressed, with increased expression in the Arctic mice relative to wildtype and decreased expression in the Arctic/C5aR1KO relative to Arctic. In addition, phagosomal-lysosomal genes were increased in the Arctic mice and further increased in the Arctic/C5aR1KO mice. These data are consistent with a microglial polarization state in the absence of C5aR1 signaling with restricted induction of inflammatory genes and enhancement of degradation/clearance pathways and support the potential of this receptor as a novel therapeutic target for AD in humans.

      Cover page: Contribution of C5aR1 to Neuroinflammation and Neuronal Dysfunction in Alzheimer’s Disease
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2005)
      Expression of C1q, an early component of the classical complement pathway, has been shown to be induced in neurons in hippocampal slices, following accumulation of exogenous Abeta42. Microglial activation was also detected by surface marker expression and cytokine production. To determine whether C1q induction was correlated with intraneuronal Abeta and/or microglial activation, D-(-)-2-amino-5-phosphonovaleric acid (APV, an NMDA receptor antagonist) and glycine-arginine-glycine-aspartic acid-serine-proline peptide (RGD, an integrin receptor antagonist), which blocks and enhances Abeta42 uptake, respectively, were assessed for their effect on neuronal C1q synthesis and microglial activation. APV inhibited, and RGD enhanced, microglial activation and neuronal C1q expression. However, addition of Abeta10-20 to slice cultures significantly reduced Abeta42 uptake and microglial activation, but did not alter the Abeta42-induced neuronal C1q expression. Furthermore, Abeta10-20 alone triggered C1q production in neurons, demonstrating that neither neuronal Abeta42 accumulation, nor microglial activation is required for neuronal C1q upregulation. These data are compatible with the hypothesis that multiple receptors are involved in Abeta injury and signaling in neurons. Some lead to neuronal C1q induction, whereas other(s) lead to intraneuronal accumulation of Abeta and/or stimulation of microglia.
        Cover page: Differential regulation of Aβ42-induced neuronal C1q synthesis and microglial activation
        • Article
        • Peer Reviewed
        UC Irvine Previously Published Works (2005)
          Cover page: Differential regulation of A beta 42-induced neuronal C1q synthesis and microglial activation
          • Thesis
          • Peer Reviewed
          UC Irvine Electronic Theses and Dissertations (2014)

          Deficiency in C1q, the recognition component of the classical complement cascade and a key opsonin involved in apoptotic cell clearance, leads to lupus-like autoimmune diseases characterized by auto-antibodies to self proteins and aberrant T and B cell activation. Studies have suggested that these pathological consequences may result from impaired clearance of apoptotic cells. To investigate how C1q may modulate inflammation resulting from diminished apoptotic cell clearance, I applied a novel system consisting entirely of primary human cells: human monocyte-derived macrophages (Mac) and dendritic cells (DC), ingesting autologous apoptotic human lymphocytes (C1q-polarized Mac; or C1q-polarized DC), and either autologous or allogeneic human T cells. This physiologically relevant experimental system enabled characterization of the C1q-polarized Mac or C1q-polarized DC functional phenotype and subsequent Mac and DC-mediated T cell activation, avoiding the caveats of other systems using either transformed cell lines or non-physiologic presentation of C1q. The results demonstrate that C1q influences intracellular signaling and gene expression of both secreted protein and cell surface receptors. That is, C1q-polarized Mac exhibited enhanced STAT1 phosphorylation that is correlated with attenuated NLRP3 inflammasome activation and sequential induction of type I IFN-s, IL-27, and IL-10 in LPS-stimulated Mac relative to Mac ingesting apoptotic lymphocytes alone. C1q-polarized DC also exhibited enhanced IL-27 expression relative to DC ingesting apoptotic lymphocytes without C1q. Under the same conditions C1q-polarized Mac showed suppressed induction of CD40 and enhanced expression of PD-L1 and PD-L2 expression while C1q-polarized DC exhibited reduced CD86 induction and elevated PD-L2 and CD39 expression relative to DC ingesting apoptotic cells alone. Finally, C1q-polarized Mac reduced allogeneic and autologous Th17 and Th1 subset proliferation, and initiated a trend towards increased regulatory T cell proliferation relative to Mac ingesting LAL alone. Moreover, relative to DC ingesting AC in the absence of C1q, C1q-polarized DC decreased autologous Th17 and Th1 proliferation. These data demonstrate that a functional consequence of C1q-polarized Mac and DC is the regulation of T effector cell activation, thereby "sculpting" the adaptive immune system to avoid autoimmunity while clearing dying cells. Importantly, these studies identify novel target pathways for therapeutic intervention in SLE and other inflammatory autoimmune diseases.

            Cover page: Complement Protein C1q: an Immunological Rheostat That Sculpts the Innate and Adaptive Immune Response During the Phagocytosis of Dying CellsCreative Commons 'BY-NC-ND' version 4.0 license
            • Article
            • Peer Reviewed
            UC Irvine Previously Published Works (2015)
              Cover page: A Commentary On: “NFκB-Activated Astroglial Release of Complement C3 Compromises Neuronal Morphology and Function Associated with Alzheimer’s Disease”. A cautionary note regarding C3aR
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2020)
              The complement cascade is a critical effector mechanism of the innate immune system that contributes to the rapid clearance of pathogens and dead or dying cells, as well as contributing to the extent and limit of the inflammatory immune response. In addition, some of the early components of this cascade have been clearly shown to play a beneficial role in synapse elimination during the development of the nervous system, although excessive complement-mediated synaptic pruning in the adult or injured brain may be detrimental in multiple neurogenerative disorders. While many of these later studies have been in mouse models, observations consistent with this notion have been reported in human postmortem examination of brain tissue. Increasing awareness of distinct roles of C1q, the initial recognition component of the classical complement pathway, that are independent of the rest of the complement cascade, as well as the relationship with other signaling pathways of inflammation (in the periphery as well as the central nervous system), highlights the need for a thorough understanding of these molecular entities and pathways to facilitate successful therapeutic design, including target identification, disease stage for treatment, and delivery in specific neurologic disorders. Here, we review the evidence for both beneficial and detrimental effects of complement components and activation products in multiple neurodegenerative disorders. Evidence for requisite co-factors for the diverse consequences are reviewed, as well as the recent studies that support the possibility of successful pharmacological approaches to suppress excessive and detrimental complement-mediated chronic inflammation, while preserving beneficial effects of complement components, to slow the progression of neurodegenerative disease.
                Cover page: The good, the bad, and the opportunities of the complement system in neurodegenerative disease
                • Article
                • Peer Reviewed
                UC Irvine Previously Published Works (2018)
                While the mechanisms underlying the functions of the complement system in the central nervous system (CNS) and systemically, namely opsonization, chemotaxis, membrane lysis, and regulation of inflammation are the same, the plethora of functions that complement orchestrates in the central nervous system (CNS) is complex. Strictly controlled expression of complement effector molecules, regulators and receptors across the gamut of life stages (embryogenesis, development and maturation, aging and disease) dictate fascinating contributions for this ancient system. Furthermore, it is becoming apparent that complement functions differ widely across distinct brain regions. This review provides a comprehensive overview of the newly identified roles for complement in the brain, including its roles in CNS development and function, during aging and in the processes of neurodegeneration. The diversity and selectively of beneficial and detrimental activities of complement, while challenging, should lead to precision targeting of specific components to provide disease modifying treatments for devastating psychiatric and neurodegenerative disorders that are still without effective treatment.
                  Cover page: New tricks for an ancient system: Physiological and pathological roles of complement in the CNS
                  • Article
                  • Peer Reviewed
                  UC Irvine Previously Published Works (2019)
                  In 2014, specific recommendations for complement nomenclature were presented by the complement field. There remained some unresolved designations and new areas of ambiguity, and here we propose solutions to resolve these remaining issues. To enable rapid understanding of the intricate complement system and facilitate therapeutic development and application, a uniform nomenclature for cleavage fragments, pattern recognition molecules (PRMs) and enzymes of the lectin pathway and regulatory proteins of the complement system are proposed, and a standardization of language to designate different activation states of complement components is recommended.
                    Cover page: Complement Nomenclature—Deconvoluted
                    • Article
                    UCSD Molecule Pages, Volume 1, Issue 2 (2012)
                    Complement C1q subcomponent subunit A (C1qA) is one of the three components of C1q molecule. Functional C1q is composed of eighteen polypeptide chains: six C1qA chains, six C1qB chains, and six C1qC chains, which are arranged as six heterotrimers of ABC: (ABC)6. Each of the individual C1q polypeptide chain consists of a N-terminal region and a C-terminal globular region (gC1q), of ~135 residues. Each N-terminal consists of 2-11 amino acid segments containing a half-cysteine residue that is involved in formation of inter-chain disulphide bonds, followed by a collagen-like region (CLR) consisting of ~81 residues. The collagen-like regions in A, B and C chains of each heterotrimer come together to form a triple helical collagen like structure. Further, A and B chains in each heterotrimer are bound by a disulphide bond, while C chain forms a disulphide bond with a C chain from the adjoining heterotrimer. Therefore the eighteen subunits come together to form six globular heads (gC1q), which are clusters of 3 independently folded C-terminal domains of the A, B and C chain. These globular domains recognize an array of self, non-self and altered-self ligands. C1q associates with the proenzymes C1r and C1s (2 molecules of each, in the molar ratio of 1:2:2 in a calcium dependent manner) to yield an active C1 complex, the first component of the serum complement system. C1r, upon binding of gC1q to an inciting stimulus, autoactivates itself and catalyzes breakage of a C1s ester bond, resulting in C1s activation and subsequent cleavage of C2 and C4 into their respective “a” and “b” fragments. Recognition of ligands by C1q molecule also defines C1q as a pattern recognition molecule (PRM). C1q recognizes distinct structures either directly on microbial structures and apoptotic cells, or indirectly after their recognition by antibodies or C-reactive protein (CRP). C1q in turn binds to multiple receptors (such as cC1qR (calreticulin), integrin α2β1 or other molecules on the surface of specific cell types of either myeloid or endothelial cell orgin) and shows regulated broad physiological functions beyond complement activation.
                    • 1 supplemental PDF
                    Cover page: Complement C1q subcomponent subunit ACreative Commons 'BY' version 3.0 license
                    Top