Microglia, Alzheimer's Disease, and Complement

Microglia, the immune cell of the brain, are implicated in cascades leading to neuronal loss and cognitive decline in Alzheimer’s disease (AD). Recent genome-wide association studies have indicated a number of risk factors for the development of late-onset AD. Two of these risk factors are an altered immune response and polymorphisms in complement receptor 1. In view of these findings, we discuss how complement signalling in the AD brain and microglial responses in AD intersect. Dysregulation of the complement cascade, either by changes in receptor expression, enhanced activation of different complement pathways or imbalances between complement factor production and complement cascade inhibitors may all contribute to the involvement of complement in AD. Altered complement signalling may reduce the ability of microglia to phagocytose apoptotic cells and clear amyloid beta peptides, modulate the expression by microglia of complement components and receptors, promote complement factor production by plaque-associated cytokines derived from activated microglia and astrocytes, and disrupt complement inhibitor production. The evidence presented here indicates that microglia in AD are influenced by complement factors to adopt protective or harmful phenotypes and the challenge ahead lies in understanding how this can be manipulated to therapeutic advantage to treat late onset AD

Immunotherapy targeting pyroglutamate-3 Aβ: prospects and challenges

Immunization against amyloid-β (Aβ) peptides deposited in Alzheimer’s disease (AD) has shown considerable therapeutic effect in animal models however, the translation into human Alzheimer’s patients is challenging. In recent years, a number of promising Aβ immunotherapy trials failed to reach primary study endpoints. Aside from uncertainties in the selection of patients and the start and duration of treatment, these results also suggest that the mechanisms underlying AD are still not fully understood. Thorough characterizations of protein aggregates in AD brain have revealed a conspicuous heterogeneity of Aβ peptides enabling the study of the toxic potential of each of the major forms. One such form, amino-terminally truncated and modified pyroglutamate (pGlu)-3 Aβ peptide appears to play a seminal role for disease initiation, qualifying it as novel target for immunotherapy approaches

Experiential learning: lessons learned from the COVID pandemic

This paper describes some innovative online and simulated solutions that were developed at Royal College of Surgeons in Ireland (RCSI) to enable continued provision of experiential learning opportunities for healthcare students during the Covid-19 pandemic. It shows how elements of experiential learning practice are amenable to virtual modes of delivery and considers the possible implications of this for experiential learning practice beyond the realm of health professions education.</div

Effector function of anti-pyroglutamate-3 Aβ antibodies affects cognitive benefit, glial activation and amyloid clearance in Alzheimer's-like mice

Background: Pyroglutamate-3 Aβ (pGlu-3 Aβ) is an N-terminally truncated and post-translationally modified Aβ species found in Alzheimer’s disease (AD) brain. Its increased peptide aggregation propensity and toxicity make it an attractive emerging treatment strategy for AD. We address the question of how the effector function of an anti-pGlu-3 Aβ antibody influences the efficacy of immunotherapy in mouse models with AD-like pathology. Methods: We compared two different immunoglobulin (Ig) isotypes of the same murine anti-pGlu-3 Aβ mAb (07/1 IgG1 and 07/2a IgG2a) and a general N-terminal Aβ mAb (3A1 IgG1) for their ability to clear Aβ and protect cognition in a therapeutic passive immunotherapy study in aged, plaque-rich APPSWE/PS1ΔE9 transgenic (Tg) mice. We also compared the ability of these antibodies and a CDC-mutant form of 07/2a (07/2a-k), engineered to avoid complement activation, to clear Aβ in an ex vivo phagocytosis assay and following treatment in APPSLxhQC double Tg mice, and to activate microglia using longitudinal microPET imaging with TSPO-specific 18F-GE180 tracer following a single bolus antibody injection in young and old Tg mice. Results: We demonstrated significant cognitive improvement, better plaque clearance, and more plaque-associated microglia in the absence of microhemorrhage in aged APPSWE/PS1ΔE9 Tg mice treated with 07/2a, but not 07/1 or 3A1, compared to PBS in our first in vivo study. All mAbs cleared plaques in an ex vivo assay, although 07/2a promoted the highest phagocytic activity. Compared with 07/2a, 07/2a-k showed slightly reduced affinity to Fcγ receptors CD32 and CD64, although the two antibodies had similar binding affinities to pGlu-3 Aβ. Treatment of APPSLxhQC mice with 07/2a and 07/2a-k mAbs in our second in vivo study showed significant plaque-lowering with both mAbs. Longitudinal 18F-GE180 microPET imaging revealed different temporal patterns of microglial activation for 3A1, 07/1, and 07/2a mAbs and no difference between 07/2a-k and PBS-treated Tg mice. Conclusion: Our results suggest that attenuation of behavioral deficits and clearance of amyloid is associated with strong effector function of the anti-pGlu-3 Aβ mAb in a therapeutic treatment paradigm. We present evidence that antibody engineering to reduce CDC-mediated complement binding facilitates phagocytosis of plaques without inducing neuroinflammation in vivo. Hence, the results provide implications for tailoring effector function of humanized antibodies for clinical development

Initial Assessment of the Pathogenic Mechanisms of the Recently Identified Alzheimer Risk Loci

Recent genome wide association studies have identified CLU, CR1, ABCA7 BIN1, PICALM and MS4A6A/MS4A6E in addition to the long established APOE, as loci for Alzheimer’s disease. We have systematically examined each of these loci to assess whether common coding variability contributes to the risk of disease. We have also assessed the regional expression of all the genes in the brain and whether there is evidence of an eQTL explaining the risk. In agreement with other studies we find that coding variability may explain the ABCA7 association, but common coding variability does not explain any of the other loci. We were not able to show that any of the loci had eQTLs within the power of this study. Furthermore the regional expression of each of the loci did not match the pattern of brain regional distribution in Alzheimer pathology. Although these results are mainly negative, they allow us to start defining more realistic alternative approaches to determine the role of all the genetic loci involved in Alzheimer’s disease