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

Abstract

Complement is involved in developmental synaptic pruning and pathological synapse loss in Alzheimer’s disease. It is posited that C1 binding initiates complement activation on synapses; C3 fragments then tag them for microglial phagocytosis. However, the precise mechanisms of complement-mediated synaptic loss remain unclear, and the role of the lytic membrane attack complex (MAC) is unexplored. We here address several knowledge gaps: (i) is complement activated through to MAC at the synapse? (ii) does MAC contribute to synaptic loss? (iii) can MAC inhibition prevent synaptic loss? Novel methods were developed and optimised to quantify C1q, C3 fragments and MAC in total and regional brain homogenates and synaptoneurosomes from WT and AppNL−G−F Alzheimer’s disease model mouse brains at 3, 6, 9 and 12 months of age. The impact on synapse loss of systemic treatment with a MAC blocking antibody and gene knockout of a MAC component was assessed in Alzheimer’s disease model mice. A significant increase in C1q, C3 fragments and MAC was observed in AppNL−G−F mice compared to controls, increasing with age and severity. Administration of anti-C7 antibody to AppNL−G−F mice modulated synapse loss, reflected by the density of dendritic spines in the vicinity of plaques. Constitutive knockout of C6 significantly reduced synapse loss in 3xTg-AD mice. We demonstrate that complement dysregulation occurs in Alzheimer’s disease mice involving the activation (C1q; C3b/iC3b) and terminal (MAC) pathways in brain areas associated with pathology. Inhibition or ablation of MAC formation reduced synapse loss in two Alzheimer’s disease mouse models, demonstrating that MAC formation is a driver of synapse loss. We suggest that MAC directly damages synapses, analogous to neuromuscular junction destruction in myasthenia gravis.

The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration

“…In contrast to modestly raised CCP activity and moderate loss of excitatory synapses in Nptx2 KO or C4-overexpressing mice, C1q and downstream complement components are highly up-regulated in many chronic neurodegenerative diseases, including AD, FTD, and Huntington’s disease ( 7 – 9 , 11 , 13 , 36 , 47 ). The marked increase in CCP activity in these diseases correlates with exacerbated synapse loss and severe neurodegeneration, and genetic or pharmacological inhibition of CCP or downstream complement components is sufficient to ameliorate neuronal damage ( 7 – 9 , 11 , 13 , 36 , 47 – 49 ). Thus, the degree of CCP activity correlates with the severity of neuronal damage across multiple diseases with different etiologies and genetic risk factors.…”

Chronic administration of XBD173 ameliorates cognitive deficits and neuropathology via 18 kDa translocator protein (TSPO) in a mouse model of Alzheimer’s disease

“…C1q has also been reported to have a specific binding site for Aβ (62). Both C1q and oligomeric Aβ act in an overlapping way to eliminate the synapses and treatment of the hippocampal slices with anti-C1q antibody significantly rescues the impairment in the LTP caused by the oligomeric Aβ (56, 63). All these studies point towards C1q playing a crucial role as a destruction signal protein in synapse elimination.…”

C1q and central nervous system disorders

“…Carpanini et al. conducted experiments on AD model mice and discovered complement dysregulation, with C1q significantly increased in the nervous system of AD mice ( 62 ). Yin et al.…”