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Published on: May 28, 2017
Targeting terminal pathway reduces brain complement activation, amyloid load and synapse loss, and improves cognition
Wioleta M Zelek1, Ryan J Bevan1, Bryan Paul Morgan1
1UK Dementia Research Institute Cardiff and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, Wales CF14 4XN, United Kingdom.
Insights
The study found that inhibiting the membrane attack complex (MAC), a component of the complement system, reduced Alzheimer
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Complement system dysregulation is observed in Alzheimer's Disease (AD) and its mouse models.
- While complement effectors like MAC are implicated in AD pathogenesis, their specific roles are unclear.
- The membrane attack complex (MAC) is a lytic and pro-inflammatory effector of the complement cascade.
Purpose of the Study:
- To investigate the role of the membrane attack complex (MAC) in Alzheimer's disease pathology using the AppNL-G-F mouse model.
- To evaluate the therapeutic potential of targeting MAC, specifically C7, for Alzheimer's disease treatment.
Main Methods:
- Generated AppNL-G-F mice deficient in C7, an essential MAC component, to ablate MAC formation.
- Administered a C7-blocking monoclonal antibody to AppNL-G-F mice to assess therapeutic efficacy.
- Assessed synapse loss, amyloid load, and cognitive performance in treated and control groups.
Main Results:
- C7 deficiency in AppNL-G-F mice reduced MAC formation, synapse loss, amyloid deposition, and improved cognition.
- Restoring C7 in deficient mice led to increased MAC formation and acute synapse loss.
- Treatment with a C7-blocking antibody decreased brain MAC and amyloid, increased synapse density, and improved cognitive function.
Conclusions:
- The membrane attack complex (MAC) acts as a significant driver of Alzheimer's disease pathology.
- Targeting MAC, via inhibition of C7, presents a promising therapeutic strategy for Alzheimer's disease.
- Complement inhibition focused on MAC components offers a potential avenue for AD treatment.
Abstract:
Complement is dysregulated in the brain in Alzheimer's Disease and in mouse models of Alzheimer's disease. Each of the complement derived effectors, opsonins, anaphylatoxins and membrane attack complex (MAC), have been implicated as drivers of disease but their relative contributions remain unclarified. Here we have focussed on the MAC, a lytic and pro-inflammatory effector, in the AppNL-G-F mouse amyloidopathy model. To test the role of MAC, we back-crossed to generate AppNL-G-F mice deficient in C7, an essential MAC component. C7 deficiency ablated MAC formation, reduced synapse loss and amyloid load and improved cognition compared to complement-sufficient AppNL-G-F mice at 8-10 months age. Adding back C7 caused increased MAC formation in brain and an acute loss of synapses in C7-deficient AppNL-G-F mice. To explore whether C7 was a viable therapeutic target, a C7-blocking monoclonal antibody was administered systemically for one month in AppNL-G-F mice aged 8-9 months. Treatment reduced brain MAC and amyloid deposition, increased synapse density and improved cognitive performance compared to isotype control-treated AppNL-G-F mice. The findings implicate MAC as a driver of pathology and highlight the potential for complement inhibition at the level of MAC as a therapy in Alzheimer's disease.
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