Terminal complement pathway activation drives synaptic loss in Alzheimer's disease models

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Complement system activation, including C1q and C3 fragments, is implicated in synaptic pruning and Alzheimer's disease (AD) pathology.
• The role of the terminal complement pathway, specifically the membrane attack complex (MAC), in AD-related synapse loss remains unexplored.

Purpose of the Study:

• To investigate whether complement is activated to MAC at synapses in AD.
• To determine if MAC contributes to synaptic loss in AD mouse models.
• To assess if inhibiting MAC formation can prevent synapse loss in AD.

Main Methods:

• Developed novel methods to quantify C1q, C3 fragments, and MAC in brain homogenates and synaptoneurosomes.
• Utilized AppNL-G-F and 3xTg-AD mouse models of Alzheimer's disease.
• Assessed synapse loss by measuring dendritic spine density and employing MAC inhibition via antibody treatment and gene knockout (C6).

Main Results:

• AppNL-G-F mice showed increased C1q, C3 fragments, and MAC with age and disease severity.
• Systemic anti-C7 antibody treatment modulated synapse loss in AppNL-G-F mice.
• Constitutive knockout of C6 significantly reduced synapse loss in 3xTg-AD mice.

Conclusions:

• Complement activation, including the terminal MAC pathway, occurs at synapses in AD mouse models.
• MAC formation is a direct driver of synapse loss in Alzheimer's disease.
• Inhibiting or ablating MAC formation offers a potential therapeutic strategy for preventing synapse loss in AD.