Targeting terminal pathway reduces brain complement activation, amyloid load and synapse loss, and improves cognition...

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 App^NL-G-F mouse model.
• To evaluate the therapeutic potential of targeting MAC, specifically C7, for Alzheimer's disease treatment.

Main Methods:

• Generated App^NL-G-F mice deficient in C7, an essential MAC component, to ablate MAC formation.
• Administered a C7-blocking monoclonal antibody to App^NL-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 App^NL-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.