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

Tenner, Andrea J.

doi:10.4049/jimmunol.1901068

Cited by 71 publications

(75 citation statements)

References 145 publications

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“…In our work, we saw reductions in hippocampal expression of C1q and C3 following mIA, across sexes, and also with protein levels of C1q, in neurons. These reductions could reflect a decrease in complement-mediated synaptic elimination (Stevens et al, 2007;Druart and Le Magueresse, 2019;Sellgren et al, 2019;Magdalon et al, 2020;Tenner, 2020). However, unlike the gene expression, C3 protein levels are increased with mIA across both sexes.…”

Section: Discussionmentioning

confidence: 97%

Sex Differences of Microglia and Synapses in the Hippocampal Dentate Gyrus of Adult Mouse Offspring Exposed to Maternal Immune Activation

Hui

Vecchiarelli

Gervais

et al. 2020

Front. Cell. Neurosci.

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Section: Discussionmentioning

confidence: 97%

Sex Differences of Microglia and Synapses in the Hippocampal Dentate Gyrus of Adult Mouse Offspring Exposed to Maternal Immune Activation

Hui

Vecchiarelli

Gervais

et al. 2020

Front. Cell. Neurosci.

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“…As mentioned above, most complement factors can be synthesized within the brain and have been shown to be elevated during progression to AD (reviewed in [ 162 , 163 ]), likely as a general response to injury that occurs in many neurological disorders. C1q was found to be dramatically increased in the normal aging of mouse and human brain [ 41 ].…”

Section: Alzheimer’s Diseasementioning

confidence: 99%

The good, the bad, and the opportunities of the complement system in neurodegenerative disease

Schartz

Tenner

2020

J Neuroinflammation

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173

183

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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.

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“…On this basis, the C5aR1 antagonist peptide PMX205 was tested in AD mouse models and reduced cognitive decline and attenuated microglial activation 131 . Therefore, if proven safe, such agents could be tested in patients with AD 132 .…”

Section: Autoimmune Encephalopathiesmentioning

confidence: 99%

Complement in neurological disorders and emerging complement-targeted therapeutics

2020

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The human complement system is an effector of innate and adaptive humoral immunity. The system comprises soluble membrane-bound proteins (opsonins) that act collectively to recognize pathogens and non-self material and subsequently initiate opsonization and phagocytosis or lysis of pathogens. The proteolytic fragments that derive from complement activation can be targeted by white blood cells and endothelial cells, leading to extravasation and migration of immune cells at the sites of inflammation. Other physiological functions of complement include timely removal of altered and senescent self, tissue remodelling, cell lysis, chemotaxis, opsonization, inflammation and immune cell stimulation 1-4. Complement activation products link the innate and adaptive immune systems by acting directly on receptors on T cells and B cells or by modulating dendritic cell functions 5-8. Disruption of the delicate coordination required for complement activation and control is fundamental in the pathogenic mechanism of several autoimmune neurological disorders, and is even emerging as a contributor in some neurodegenerative diseases. As a result, interest is increasing in targeting complement as a therapeutic approach to prevent ongoing tissue destruction in several difficult-to-treat neurological diseases. In this Review, we provide an overview of the main components of the initial complement activation pathways, the lytic pathway and the factors associated with inappropriate complement activation or control in disease initiation and progression. We consider the role of complement in the tissue destruction that is responsible for the genesis of the most common autoimmune neurological diseases, including complement-mediated myopathies, myasthenia gravis, neuropathies and CNS disorders. We also discuss the role of complement in some neurodegenerative disorders, including Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), Huntington disease, traumatic brain injury and even schizophrenia. Finally, we discuss emerging complement-targeted therapies, such as monoclonal antibodies, fusion proteins and cyclic peptides, that inhibit the functions of individual complement proteins, especially therapies that disrupt the lytic pathway. Some of these therapeutic agents have been approved or are being tested in phase I-III clinical trials and promise to change the therapeutic armamentarium for treatment of neurological conditions that respond poorly to existing immunotherapies.

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

Cited by 71 publications

References 145 publications

Sex Differences of Microglia and Synapses in the Hippocampal Dentate Gyrus of Adult Mouse Offspring Exposed to Maternal Immune Activation

Sex Differences of Microglia and Synapses in the Hippocampal Dentate Gyrus of Adult Mouse Offspring Exposed to Maternal Immune Activation

The good, the bad, and the opportunities of the complement system in neurodegenerative disease

Complement in neurological disorders and emerging complement-targeted therapeutics

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